Pigment Cell Melanoma Res. 26; 176–192 REVIEW ARTICLE

Hermansky–Pudlak syndrome: pigmentary and non-pigmentary defects and their pathogenesis Ai-Hua Wei1,2 and Wei Li2

1 Department of Dermatology, Beijing Tongren Affiliated Hospital of Capital Medical University, Beijing, China KEYWORDS Hermansky–Pudlak syndrome/lyso- 2 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, some-related organelles/signal transduction/lyso- Chinese Academy of Sciences, Beijing, China somal trafficking/hypopigmentation

CORRESPONDENCE W. Li, e-mail: [email protected]; A.-H. Wei, email: [email protected] PUBLICATION DATA Received 13 September 2012, revised and accepted for publication 16 November 2012, published online 16 November 2012

doi: 10.1111/pcmr.12051

Summary Hermansky–Pudlak syndrome (HPS) is an autosomal recessive and genetically heterogeneous disorder characterized by oculocutaneous albinism, bleeding tendency, and ceroid deposition, which likely leads to deleterious lesions in lungs, heart, and other organs. Currently, nine genes have been identified as causative for HPS in humans. Their pathological effects are attributable to the disrupted biogenesis of lysosome-related organelles (LROs) existing in multiple cell types or tissues, causing the pigmentory and non-pigmentory defects. This review focuses on the functional aspects of HPS genes in regulating LRO biogenesis and signal transduction. The understanding of these mechanisms expands our knowledge about the involvement of lysosomal trafficking in the targeting of cargoes for constitutive transport, degradation, and secretion. This opens an avenue to the pathogenesis of lysosomal trafficking disorders at the cellular and developmental levels.

Introduction to Hermansky–Pudlak order. Nine genes (HPS1, AP3B1, and HPS3 to HPS9) syndrome have been identified as causative genes for HPS in humans (Anikster et al., 2001; Cullinane et al., 2011a; Clinical features and overview of Hermansky–Pudlak Dell’Angelica et al., 1999; Li et al., 2003; Morgan et al., syndrome 2006; Oh et al., 1996; Suzuki et al., 2002; Zhang et al., Hermansky–Pudlak syndrome (HPS, OMIM 203300; 2003). Additional six genes (Ap3d, Rabggta, Vps33a, Cno, Hermansky and Pudlak, 1959) is an autosomal recessive Muted, Kxd1) cause mouse HPS (Li et al., 2004; Yang disorder characterized by oculocutaneous albinism (OCA), et al., 2012) and are listed in the HPS database (HPSD, bleeding tendency, and ceroid deposition, which may http://liweilab.genetics.ac.cn/HPSD/; Li et al., 2006). As cause lung fibrosis, colitis, and cardiomyopathy in some the HPS proteins have been categorized into several cases. Patients with HPS often die during the third to fifth lysosomal-trafficking protein complexes such as AP-3, decade (Huizing and Gahl, 2002; Huizing et al., 2000). The HOPS, BLOC-1, BLOC-2, and BLOC-3 (Di Pietro and key pathological aspect of both human and mouse HPS is Dell’Angelica, 2005; Li et al., 2004), genes encoding the the disrupted biogenesis and/or function of lysosome- subunits of these complexes that have not been defined related organelles (LROs), including melanosomes and as HPS proteins are putative HPS genes, as evidenced by platelet-dense granules (DG) as well as secretory lyso- the discovery of the HPS9 gene (Cullinane et al., 2011a). somes (Dell’Angelica et al., 2000; Huizing et al., 2008; Li et al., 2004; Swank et al., 1998; Wei, 2006). Incidence Hermansky–Pudlak syndrome occurs in many countries, Genetics with more than 800 patients reported worldwide. It is Hermansky–Pudlak syndrome is now known as a genet- almost certainly underestimated because of mis-diagno- ically heterogeneous, autosomal recessive inherited dis- sis or un-diagnosis. The highest prevalence region of HPS

176 ª 2012 John Wiley & Sons A/S Hermansky–Pudlak syndrome is in Puerto Rico with founder effects. The incidence rate diagnoses are now available with the identification of nine is estimated as 1:1800 with a carrier rate of 1:21 in HPS genes in humans. Chediak–Higashi syndrome (CHS, Puerto Rico (Oh et al., 1996). HPS-1 and HPS-3 are the OMIM #214500) exhibits similar defects on the biogen- two common types of HPS in this region (Anikster et al., esis of LROs due to the mutation on the CHS1/LYST gene 2001). Non-Puerto Rican patients with HPS are scattered (Barbosa et al., 1996). Mortality of CHS in childhood often in many populations as listed in the HPSD database. results from frequent bacterial infections due to immu- HPS-1 is the relatively common subtype in Japanese (Ito nodeficiency or from an ‘accelerated phase’ lymphopro- et al., 2005) and Chinese OCA patients (Wei et al., 2010, liferation into the major organs of the body (Blume and 2011). Wolff, 1972). Patients exhibiting milder clinical pheno- types survive to adulthood but develop progressive and Pathogenesis often fatal neurological dysfunction (Karim et al., 2002). The pathogenesis underlying HPS results from defects in Griscelli syndrome (GS, OMIM #214450) also presents the biogenesis of LROs, which are described in more with hypopigmentation, immunological impairment, lym- detail later. phohistiocytosis, or defects in the central nervous system (Meeths et al., 2010), but lacks defects in platelet DG Clinical manifestation (Chintala et al., 2007). Griscelli syndrome is caused by Symptoms of HPS in humans have been reviewed mutation of GS1/MYO5A (Pastural et al., 1997), GS2/ extensively (DePinho and Kaplan, 1985; Huizing et al., RAB27A (Menasche et al., 2000), or GS3/MLPH (Mena- 2008; Spritz, 2000). In 1959, two Czechoslovakian physi- sche et al., 2003). Molecular diagnosis and EM examina- cians Hermansky and Pudlak first described the pigmen- tion of platelet-DG in patients with CHS or GS allow tary and non-pigmentary abnormalities in HPS accurate differentiation from HPS (Table 1). (Hermansky and Pudlak, 1959). The most common symptoms of HPS are hypopigmentation, loss of visual Mutations in HPS genes acuity, prolonged bleeding, colitis, and, in some cases, Through positional candidate cloning, the first human HPS fatal lung disease. Hemophagocytic lymphohistocytosis gene, HPS1, was identified in 1996 (Oh et al., 1996). This (Enders et al., 2006) and immune deficiency (Huizing prompted the identification of the first murine HPS gene, et al., 2002) have been reported in patients with HPS-2. Hps1/ep (Gardner et al., 1997; Spritz, 2000), and the Neuronal symptoms are described in Ap3b1-deficient and cloning of 14 other HPS genes in mouse and eight human Ap3b2-deficient mice (Seong et al., 2005). Participation of HPS genes thereafter (Table 2). Currently, proteins mouse AP-3 and BLOC-1 in synaptic vesicle biogenesis encoded by these human or murine HPS genes fall into implicates potential neuronal dysfunction in patients with several protein complexes in regulating vesicle trafficking HPS (Chen et al., 2008; Larimore et al., 2011; Newell- in the endo-lysosomal system as summarized in several Litwa et al., 2010). Although the dysbindin-null sdy reviews (Di Pietro and Dell’Angelica, 2005; Huizing et al., mutant has been characterized as a mouse model of 2008; Li et al., 2004; Sitaram and Marks, 2012; Wei, schizophrenia (Cox et al., 2009; Feng et al., 2008), the 2006). That is HPS1 and HPS4 in BLOC-3; AP3B1/HPS2 patient with HPS-7 did not show symptoms related to and AP3D in AP-3; HPS3, HPS5, and HPS6 in BLOC-2; schizophrenia (Li et al., 2003). No pathological mutation HPS7, HPS8, HPS9, MUTED and CNO in BLOC-1. of the HPS7/DTNBP1 gene has been identified yet in VPS33A is a subunit of HOPS. RABGGTA is the a-subunit patients with schizophrenia. of Rab geranylgeranyl transferase which is involved in the prenylation of Rab proteins. KXD1 is a BLOC-1 interactor Prognosis that likely causes mild-form HPS when mutated (Yang Prolonged bleeding often requires multiple platelet trans- et al., 2012). The cloning history of these HPS genes is fusions, and the fibrotic lung disease may lead to death in listed in Table 2. midlife. Table 1. Syndromic dysgenesis of lysosome-related organelles Therapy Specialized LROs Dysfunction Syndromes There is presently no cure for HPS. Only symptomatic (e. g., sunscreen to avoid sunburn, platelet transfusion and Melanosomes Oculocutaneous HPS, CHS, GS use of desmopressin in the correction of prolonged albinism (hypopimentation) bleeding) treatments for the disease exist. Stem cell Platelet granules Bleeding diathesis HPS, CHS therapy may be promising in alleviating symptoms such Synaptic vesicles Abnormal behaviors HPS-2, CHS, GS as bleeding and visual loss. Neurological symptoms Lytic granules Immunodeficiency HPS-2, CHS, GS Azurophil granules Neutropenia HPS-2, CHS Diagnosis Lamellar bodies Lung fibrosis HPS-1, HPS-4 The gold standard of HPS is the absence of platelet-DG upon electron microscopy (EM). Symptoms of hypopig- CHS, Chediak–Higashi syndrome; GS, Griscelli syndrome; HPS, mentation and bleeding support the diagnosis. Molecular Hermansky–Pudlak syndrome; LRO, lysosome-related organelles.

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Table 2. The identified nine human and 15 mouse HPS genes

HPS subtype Human locus Mouse mutant Protein function References of cloning

HPS-1 HPS1 pale-ear (ep) BLOC-3 subunit Gardner et al. (1997), Oh et al. (1996) HPS-2 HPS2/AP3B1 pearl (pe) AP-3 subunit Dell’Angelica et al. (1999), Feng et al. (1997) HPS-3 HPS3 cocoa (coa) BLOC-2 subunit Anikster et al. (2001), Suzuki et al. (2001) HPS-4 HPS4 light-ear (le) BLOC-3 subunit Suzuki et al. (2002) HPS-5 HPS5 ruby-eye 2 (ru2) BLOC-2 subunit Zhang et al. (2003) HPS-6 HPS6 ruby-eye (ru) BLOC-2 subunit Zhang et al. (2003) HPS-7 HPS7/DTNBP1 sandy (sdy) BLOC-1 subunit Li et al. (2003) HPS-8 HPS8/BLOC1S3 reduced BLOC-1 subunit Morgan et al. (2006), pigmentation (rp) Starcevic and Dell’Angelica (2004) HPS-9 HPS9/PLDN pallid (pa) BLOC-1 subunit Cullinane et al. (2011a), Huang et al. (1999) – MUTED muted (mu) BLOC-1 subunit Zhang et al. (2002a) – CNO cappuccino (cno) BLOC-1 subunit Ciciotte et al. (2003) – KXD1 Kxd1-KO BLOC-1 interactor Yang et al. (2012) – AP3D mocha (mh) AP-3 subunit Kantheti et al. (1998) – VPS33A buff (bf) HOPS subunit Suzuki et al. (2003b) – RABGGTA gunmetal (gm) Rab geranylgeranyl Detter et al. (2000) transferase alpha subunit

HPS, Hermansky–Pudlak syndrome. KO, knockout. BLOC-1, biogenesis of lysosome-related organelles complex-1. BLOC-2, biogenesis of lysosome-related organelles complex-2. BLOC-3, biogenesis of lysosome-related organelles complex-3. AP-3, adaptor protein complex-3. HOPS, homotypic fusion and protein sorting complex.

HPS1 the absence of platelet-DG (Figure 1), a gold standard for The HPS1 gene is located on chromosome 10q24.2. It the diagnosis of HPS. contains 20 exons (NCBI RefSeq: NM_000195), encoding a 700-aa HPS1 protein. There are three other transcription HPS2/AP3B1 variants. Thirty-one alleles that cause HPS-1 have been The HPS2 gene is located on chromosome 5q14.1. It identified and listed in the HPSD database. Most of the contains 27 exons (NCBI RefSeq: NM_003664), encoding HPS1 gene mutations are frameshift mutations or non- a 1094-aa AP3B1 protein, the b-subunit of the ubiquitous sense mutations to produce truncated HPS1 proteins that AP-3 complex (b3A). Eleven alleles that cause HPS-2 have disrupt the function of the HPS1 protein (Hermos et al., been identified and listed in the HPSD database. Most of 2002; Oh et al., 1996, 1998). HPS1, together with HPS4, the HPS2 gene mutations are frameshift mutations or is an obligate subunit of BLOC-3. Loss of either subunit nonsense mutations to produce truncated AP3B1 pro- results in destabilization of the remaining subunits (Suzuki teins that disrupt the function of the AP3B1 protein, et al., 2002). Two missense mutations (p.L239P and p. leading to the complete absence of b3A subunit and the L668P) have been reported. Overexpression of L668P- destabilization of other AP-3 subunits (Clark et al., 2003; mutant HPS1 protein in HPS1-null melanocytes did not Dell’Angelica et al., 1999; Fontana et al., 2006; Huizing restore the stability of endogenous HPS4, suggesting this et al., 2002). missense substitution is pathologic (Ito et al., 2005). Interestingly, the c.1932delC mutation leads to a longer HPS3 HPS1 protein in which a novel 79-residue peptide The HPS3 gene is located on chromosome 3q24. It replaces the wild-type 56-residue peptide after the contains 17 exons (NCBI RefSeq: NM_032383), encoding mutation site at D644 (Wei et al., 2009). A similar a 1004-aa HPS3 protein. Eight alleles that cause HPS-3 elongated HPS1 protein is predicted for the c.1885delC have been identified and listed in the HPSD database. mutation (Wei et al., 2011). In our Western blots, the Most of the HPS3 gene mutations are frameshift muta- elongated HPS1 protein is absent (Figure 1), indicating tions or splicing mutations to produce truncated HPS3 that the extension destabilizes the protein and is patho- proteins that disrupt the function of the HPS3 protein and logic. The patient who carries the homozygous BLOC-2 (Anikster et al., 2001; Boissy et al., 2005; Huizing c.1932delC mutation shows typical OCA symptoms and et al., 2001a).

178 ª 2012 John Wiley & Sons A/S Hermansky–Pudlak syndrome

A C

B D

Figure 1. Feature of a Chinese HPS-1 patient with the c.1932delC homozygous mutation. (A) The 2-yr-old girl with HPS1 who was diagnosed with a homozygous c.1932delC mutation in the HPS1 gene, shows hypopigmentation in skin and hair (Wei et al., 2009). (B) Hypopigmentation in the retinas of this HPS-1 patient (lower panel) compared with normal pigmented retinas (upper panel; Wei et al., 2009). (C) Lack of dense granules in the patient’s whole-mount platelets. This electron microscopy (EM) examination was done by Dr. Ling Yang and Ms. Zhe Zhang. (D) The homozygous c.1932delC mutation of the HPS1 gene leads to the loss of the 80 kD HPS1 protein, without the expected larger band of the predicted elongated HPS1 protein on the blot in the patient’s platelets. The monoclonal mouse HPS1 antibody used in this immunoblotting assay was a gift of Dr. Richard A. Spritz. This assay was assisted by Ms. Zhe Zhang. This study was approved by the IRB of Beijing Tongren Hospital. The subjects in this study gave written informed consent. HPS, Hermansky–Pudlak syndrome.

HPS4 HPS-6 have been identified and listed in the HPSD The HPS4 gene is located on chromosome 22q12.1. It database. Most of the HPS6 gene mutations are frame- contains 14 exons (NCBI RefSeq: NM_022081), encod- shift or nonsense mutations that disrupt the function of ing a 708-aa HPS4 protein. Four alternative transcription HPS6 protein and BLOC-2 (Huizing et al., 2009; Zhang variants exist that differ in the 5′-UTR and coding regions et al., 2003). compared to NM_022081. Thirteen alleles that cause HPS-4 have been identified and listed in the HPSD HPS7/DTNBP1 database. Most of the HPS4 gene mutations are The HPS7 or DTNBP1 gene is located on chromosome frameshift mutations or nonsense mutations to produce 6p22.3. It contains 10 exons (NCBI RefSeq: NM_032122), truncated HPS4 proteins that disrupt the function of the encoding a 351-aa dysbindin-1a protein. NM_183040 HPS4 protein and BLOC-3 (Anderson et al., 2003; Bachli contains an additional segment in the coding region et al., 2004; Carmona-Rivera et al., 2011; Suzuki et al., compared to NM_032122. The resulting 303-aa dysbin- 2002). din-1b contains a shorter and distinct C-terminus com- pared to dysbindin-1a. NM_183041 contains an alternate splice site in the 5′ coding region and uses a downstream HPS5 start codon, compared to NM_032122. The encoded 270- The HPS5 gene is located on chromosome 11p15.1. It aa isoform dybindin-1c has a shorter N-terminus com- contains 23 exons (NCBI RefSeq: NM_181507), encoding pared to dysbindin-1a. In addition, three dysbindin-2 a 1129-aa HPS5 protein. Two alternative transcription isoforms and two dysbindin-3 isoforms were docu- variants exist that encode a 1015-aa HPS5 isoform. mented (Tang et al., 2009a; Talbot et al., 2009a). To date, Eleven alleles that cause HPS-5 have been identified only one homozygous nonsense mutation, p.Q103X, has and listed in the HPSD database. Most of the HPS5 gene been reported in a patient with HPS-7 (Li et al., 2003). mutations are frameshift mutations that show severely decreased HPS5 mRNA, attributable to nonsense-medi- HPS8/BLOC1S3 ated decay (Huizing et al., 2004; Zhang et al., 2003). The HPS8 gene is located on chromosome 19q13.32. It contains only one exon (NCBI RefSeq: NM_212550), HPS6 encoding a 202-aa BLOS3 protein. Two alleles that cause The HPS6 gene is located on chromosome 10q24.32. It HPS-8 have been identified and listed in the HPSD contains only one exon (NCBI RefSeq: NM_024747), database. No nonsense-mediated decay and destabiliza- encoding a 775-aa HPS6 protein. Nine alleles that cause tion of the BLOC-1 complex was observed to the p.S44X

ª 2012 John Wiley & Sons A/S 179 Wei & Li and p.Q150delC mutation (Cullinane et al., 2012; Morgan With the discovery of murine and human HPS genes, et al., 2006). three biogenesis of lysosome-related organelles com- plexes (BLOC-1, BLOC-2, and BLOC-3) have been HPS9/PLDN defined. That is, pallidin, muted, dysbindin, cappuccino, The HPS9 gene is located on chromosome 15q21.1. It snapin, BLOS1, BLOS2, and BLOS3 in BLOC-1 (Ciciotte contains five exons (NCBI RefSeq: NM_012388), encoding et al., 2003; Falcon-Perez et al., 2002; Gwynn et al., a 172-aa HPS9 protein. To date, only one homozygous 2004; Li et al., 2003; Starcevic and Dell’Angelica, 2004); nonsense mutation, p.Q78X, has been reported in a patient HPS3, HPS5, and HPS6 in BLOC-2 (Di Pietro et al., 2004; with HPS-9 (Cullinane et al., 2011a). The p.Q78X mutation Gautam et al., 2004; Zhang et al., 2003); and HPS1 and does not cause nonsense- mediated decay directly but HPS4 in BLOC-3 (Chiang et al., 2003; Martina et al., results in the skipping of exon3 (Cullinane et al., 2011a). 2003; Nazarian et al., 2003; Suzuki et al., 2002). The biochemical features and assembling machineries of Mouse models of HPS these BLOC complexes remain to be defined, although A major contribution of Dr. Richard T. Swank’s laboratory some pioneering studies have revealed binding domains was the collection, since the 1970s, of mouse mutants in building these BLOCs (Dell’Angelica, 2004; Li et al., that mimic the human HPS phenotypes. Additional 2007) and the linear assembly of the BLOC-1 complex phenotypes such as susceptibility to anesthetics, protec- in vitro (Lee et al., 2012). Together with the well-known tion from atherosclerosis, and otolith deficiency have AP-3 (adaptor protein complex-3) and HOPS (homotypic been documented only in mouse HPS mutants as fusion and protein sorting complex) complexes, the BLOC summarized in (Li et al., 2004; Swank et al., 1998). The complexes function in endo-lysosomal trafficking. Emerg- characterization of more than a dozen mouse HPS ing evidence has shown that these complexes direct mutants (Swank et al., 1998) led to a series of successful cargoes from either de novo synthesis or endocytosis into identifications of murine and human HPS genes (Li et al., lysosomes and LROs. In addition, whether there is a 2004; Table 2). Currently, the 15 cloned mouse HPS master regulator to coordinate the action of these genes are known to reside in several HPS Protein complexes remains unknown. A key to understanding Associated Complexes (HPAC, shown in Table 2 and LRO biogenesis is to define the behaviors of these Figure 2) to mediate the biogenesis of LROs. interacting complexes. An intriguing question is whether

Figure 2. Illustration of the HPS protein associated complexes (HPAC). Seven HPACs are depicted based on the current understanding of the structural assembly and physical interactions described in the text. BLOC-1 is assembled linearly connected by two subcomplexes (BLOS1- pallidin-cappuccino and BLOS2-dysbindin-snapin), with muted and BLOS3 overhung. KXD1 is a BLOC-1 interactor bound to BLOS1. In BLOC-2, HPS3, HPS5, and HPS6 interact with each other. HPS1 and HPS4 are tightly bound in BLOC-3. In the HOPS complex, VPS18 connects the head (VPS16-VPS33A-VPS41) and tail (VPS11 and VPS39). The ubiquitous AP-3 complex contains the b3A, d, l3A and r3 subunits. The core Rab GGTase II enzyme consists of a and b subunits. In the RabGGTase II holoenzyme, REP-1 (or component A) binds unprenylated Rab proteins and then presents them to the catalytic Rab GGTase II for the geranylgeranyl transfer reaction. The protein names with a star sign (*) indicate mutations in human and mouse HPS, those with a pound sign (#) indicate mutations in mouse HPS only. A question mark on the RAB38 indicates an unresolved HPS protein. HPS, Hermansky–Pudlak syndrome.

180 ª 2012 John Wiley & Sons A/S Hermansky–Pudlak syndrome these complexes act synergistically or sequentially on the VPS41 homolog VPS8 and the VPS39 homolog VPS3. cargo transport. Double or multiple mouse mutants The CORVET and HOPS complexes interconvert through played a pivotal role in dissecting these interactions as two intermediate complexes consisting of the class C evidenced by epistatic or synergistic effects on coat color core bound to VPS39-VPS8 or VPS3-VPS41 (Peplowska or LRO phenotypes (Gautam et al., 2006; Hoyle et al., et al., 2007). In the HOPS complex, the large head 2011). At the cellular level, the mouse HPS mutants contains VPS41, VPS33, and VPS16, whereas Vps39 is provide powerful tools for the dissection of cargo-specific found in the tip of its tail, with VPS11 and VPS18 endo-lysosomal-trafficking pathways in different tissues. connecting the head and tail (Brocker et al., 2012). VPS33 As revealed by spontaneous murine HPS mutants, one is a Sec1-/Munc18-like protein that interacts with would expect the development of HPS when generating SNAREs. In metazoans, two homologs, VPS33A and knockout mutants for the remaining subunits of the VPS33B, are present. It is uncertain whether VPS33B is a HPACs. While the mutants of known subunits of BLOC-2 component of the COVERT complex (Zlatic et al., 2011), and BLOC-3 are murine HPS models (Li et al., 2004), it is while VPS33A is a part of the HOPS complex (Sriram unknown whether mutation of the genes encoding et al., 2003). Mutation of Vps33a in the bf mice leads to snapin, BLOS1, and BLOS2 in the BLOC-1 complex HPS with additional neurological lesions, although the would cause typical HPS. In contrast, the snapin knockout underlying mechanism leading to Purkinje cell loss and (KO) mice died at the perinatal stage, which is unlike neurological atrophy is unknown (Chintala et al., 2009; other BLOC-1 mutants and showed developmental Suzuki et al., 2003b). A mutation in human VPS33B defects of the central nervous system (Tian et al., 2005; causes arthrogryposis-renal dysfunction-cholestasis syn- Zhou et al., 2011). This suggests that snapin may play drome but not HPS (Gissen et al., 2004). Again, this extra roles independent of BLOC-1. Whether the BLOS1 suggests that distinct mammalian Vps-C complexes or BLOS2 knockout mice exhibit typical HPS phenotypes function differently. with comparable survival remains to be investigated. The HPS mouse model gunmetal (gm) is deficient in Interestingly, multiple isoforms of dysbindin have been the a-subunit of Rab GGTase II (RABGGTA; Detter et al., shown both in human and mouse tissues (Talbot et al., 2000). Together with the b-subunit and an escort protein, 2009). Studies have shown the different distribution REP-1, RABGGTA adds two geranyl 10-carbon isoprenoid pattern of these isoforms in developmental stages and groups to the C-termini of Rab proteins (Anant et al., in sub-brain regions and sub-synaptic regions (Ito et al., 1998). In gm mutant, the prenylation of Rab proteins 2010; Talbot et al., 2011; Tang et al., 2009a). The (such as Rab27a, 11a, and 4) is deficient in platelets and involvement of dysbindin in the dystrobrevin complex melanocytes (Zhang et al., 2002b), which may explain the (Benson et al., 2001) and WAVE2-Abi-1 complex (Ito defects in the biogenesis of platelet granules and mela- et al., 2010) has raised the question whether all these nosomes, thus mimicking the symptoms of HPS. Cur- isoforms function in a BLOC-1-dependent manner. rently, no RABGGTA mutation has been reported in The AP-3 complex is a heterotetramer composed of patients with HPS or storage pool deficiency (Li et al., two large adaptins (AP3D1/d and AP3B1/b3A or AP3B2/ 2000). However, mutations in the CHM gene that b3B), a medium adaptin (AP3M1/l3A or AP3M2/l3B), encodes REP-1 are a cause for choroideremia (also and a small adaptin (AP3S1/r3A or AP3S2/r3B). There known as tapetochoroidal dystrophy). This X-linked dis- exist two types of mammalian AP-3 complexes: a ease is characterized by progressive dystrophy of the ubiquitous AP-3 comprising AP3D1-AP3B1-AP3M1- choroid, retinal pigment epithelium, and retina (Sankila AP3S1 (or AP3S2) subunits and a brain-specific AP-3 et al., 1992). Defective Rab prenylation and depigmenta- complex containing AP3D1-AP3B2-AP3M2-AP3S1 (or tion occur in Chm knockout mice (Tolmachova et al., AP3S2) subunits as summarized in a recent review 2006). (Dell’Angelica, 2009). In mice, only mutation of the RAB38 forms a complex with VARP in mediating the Ap3b1 (in pearl mice) or Ap3d1 (in mocha mice) have melanosomal transport of TYRP1 (Tamura et al., 2009; been shown to present HPS phenotypes (see Table 2). Wang et al., 2008). Mutation of the melanosomal protein Knockout of the neuron-specific Ap3b2 or Ap3m2 results RAB38 in chocolate (cht) mice causes dilution in coat in neurological impairments but not HPS (Nakatsu et al., color (Loftus et al., 2002) and ocular hypopigmentation 2004; Newell-Litwa et al., 2009; Seong et al., 2005). This (Brooks et al., 2007), suggesting that cht is a mouse leads to the notion that tissue-specific complexes are model of OCA. In addition, defects in melanosomes formed to execute special physiological functions. (Brooks et al., 2007) and lamellar bodies (LBs; Osanai The class C Vps complexes (HOPS and CORVET) are et al., 2008) were observed in cht mice, suggesting that involved in homotypic fusion and tethering during en- RAB38 is a candidate HPS gene affecting multiple LROs dosomal trafficking (Nickerson et al., 2009). Both HOPS (Brooks et al., 2007; Osanai and Voelker, 2008). Consis- and CORVET complexes share the four Vps proteins tent with this possibility, the rat RAB38 is null in Fawn- (class C core), VPS11-VPS16-VPS18-VPS33. The HOPS Hooded and Tester-Moriyama rats which mimic the complex contains in addition two Rab-binding proteins, human HPS phenotype (Oiso et al., 2004). Other evi- VPS41 and VPS39, whereas the CORVET complex has dence to show the involvement of RAB38 in the devel-

ª 2012 John Wiley & Sons A/S 181 Wei & Li opment of HPS is the interactions between RAB38 and HPS genes in the biogenesis of lysosome- BLOC-1, BLOC-2, and AP-3, which likely transport the related organelles cargoes of BLOC-2, AP-3, and AP-1 into melanosomes (Bultema et al., 2012). In addition, BLOC-3 has been Lysosome-related organelles shown to function as a guanine nucleotide exchange Lysosomes are membrane-bound cytoplasmic organelles factor for RAB38 and RAB32 (Gerondopoulos et al., that are found in all mammalian cells and contain 2012). Taken together, these data suggest that RAB38 hydrolases and lipases required for protein and mem- and RAB32 function with other HPS protein complexes, brane degradation. They are characterized by soluble acid- implicating the loss-of-function of RAB38 or RAB32 may dependent hydrolases and a set of highly glycosylated develop similar phenotypes as HPS. However, no pro- integral membrane proteins such as lysosome-associated longed bleeding times or blood defects occur in cht mice membrane proteins (LAMPs). Many properties of lyso- (Brooks et al., 2007; Loftus et al., 2002). One possible somes such as acidic lumenal pH, LAMPs, and high explanation is a hypermorphic effect in cht mice. The intralumenal Ca2+ concentrations are likely shared by a existing mutant hydrophilic RAB38 (Osanai et al., 2008) group of cell type-specific compartments referred to as may function in platelets without affecting the biogenesis ‘LROs’, which include melanosomes, platelet-DG, Weibel of DG. Another explanation is redundant function of a –Palade bodies (WPB), and large dense core vesicles RAB38 homolog, RAB32, in platelets (Wasmeier et al., (Table 3 and Figure 3; Li et al., 2004). In addition to 2006). In a recent study, RAB38 and RAB32 are involved lysosomal proteins, these organelles contain cell type- in the cargo vesicle fusion with mature organelles during specific components that are responsible for their spe- the biogenesis of platelet-DG (Ambrosio et al., 2012). cialized functions (Dell’Angelica et al., 2000; Raposo Currently, no mutation of the RAB38 gene has been et al., 2007). Lysosome-related organelles feature cell reported in patients with HPS or OCA (Brooks et al., type-specific morphology and functions and may undergo 2007; Suzuki et al., 2003a). regulated secretion (also called secretory lysosomes). Misty (m) mice show generalized hypopigmentation They can co-exist with lysosomes in some cells like and prolonged bleeding times similar to HPS mouse melanocytes and platelets. mutants (Sviderskaya et al., 1998; Swank et al., 1998), but no evidence of a generalized LRO anomaly (Blasius Cargo-specific trafficking to lysosomes, et al., 2009). Thus, the mutation of Dock7 (a Rho family melanosomes, and other LROs guanine nucleotide exchange factor) in misty mice HPS genes in the biogenesis of lysosomes (Blasius et al., 2009) is unlikely to cause murine HPS. Lysosomal biogenesis has puzzled scientists since the The subtle gray (sut) mouse was regarded as a model for definition of lysosome. A transcription factor EB (TFEB) a mild form of HPS (Swank et al., 1996, 1998). However, has been reported to be the master regulator of lyso- the hypopigmentation is mainly caused by the reduction somal biogenesis (Sardiello et al., 2009). Putative pro- in pheomelanin production due to the mutation of the moter regions of HPS genes may be regulated by TFEB or Slc7a11 gene which encodes the functional subunit of other transcription factors (Palmieri et al., 2011; Stanescu the cystine/glutamate antiporter, xCT (Chintala et al., et al., 2009). The well-known function of lysosomes is the 2005). Although the function of xCT in the biogenesis of platelet-dense granule has not been intensively studied, no generalized LRO anomaly in sut mice has been Table 3. Lysosome-related Organelles (LROs) described, excluding it as a typical mouse HPS model. The ashen (ash) line maintained at Roswell Park Cancer Organelles Tissue distribution Institute (referred as ash-Roswell) that was regarded as a Secretory lysosomes Ubiquitous mouse model of HPS (Li et al., 2004; Wilson et al., 2000) Melanosomes Melanocytes has been identified to be a double mutant with mutations Platelet-dense granules Platelets in both the Rab27a gene and the Slc35d3 gene (Chintala Weibel–Palade bodies Endothelial cells et al., 2007; Wilson et al., 2000). The deficiency in Large-dense core vesicles Adrenal chromaffin cells Rab27a causes a defect in melanosomal transport which Synaptic vesicles Neurons leads to hypopigmentation (Wilson et al., 2000), while the Insulin granules Pancreatic islets Lamellar bodies Alveolar type II epithelial cells deficiency of Slc35d3 leads to defects in the biogenesis Lytic granules NK cells, Cytotoxic T lymphocytes of platelet-DG (Chintala et al., 2007; Meng et al., 2012). MHC-II compartments Antigen-presenting cells The Rab27a mutation does not cause defects in platelet- Basophilic granules Mast cells DG or prolonged bleeding (Barral et al., 2002). In contrast, Azurophilic granules Neutrophils, Eosinophils hypopigmentation is not seen in the Roswell (ros)-mutant Osteoclast granules Osteoclasts mice, which carry only the Slc35d3 mutation. SLC35D3 Renin granules Juxtaglomerula cells Acrosomes Spermatozoa may not be expressed in melanocytes (our unpublished Otic vesicles Inner ear cells data). Thus, the identified HPS mouse models have been Fusiform vesicles Urothelial umbrella cells updated to 15 lines as listed in Table 2.

182 ª 2012 John Wiley & Sons A/S Hermansky–Pudlak syndrome

A C

B D Figure 3. Representative electron microscopic pictures of lysosome-related organelles (LROs) in mouse tissues. (A) Melanosomes in retinal pigment epithelium (RPE) and choroid. (B) Dense granules (DGs) in whole-mount platelet. (C) Weibel– Palade bodies (WPBs) in endothelial cells in longitudinal section (upper) and transverse section (lower). (D) Large-dense core vesicles (LDCVs) in adrenal chromaffin cells. Arrows in the images indicate the representative LROs. degradation of transported cargoes via the endo-lyso- This may explain why the existing BLOC-1- or AP-3- somal-trafficking system. However, its function is broad- mutant mice are viable without apparent lesions in ened especially in autophagy, phagocytosis, and tissues like liver and heart. BLOC-1 and AP-3 either exocytosis as summarized in a recent review (Boya, facilitate delivery of a cohort of lysosomal membrane 2012). How constitutive membrane proteins and luminal proteins to lysosomes or enhance the efficiency of proteins are directed into lysosomes is not well defined, lysosomal delivery. A more plausible mechanism of the although accumulating data have revealed that this roles of BLOC-1 and AP-3 in lysosomal protein trafficking process may utilize the machinery of endo-lysosomal is that they coordinate LAMPs for degradation in conven- trafficking. In HPS, the function of lysosomes is disturbed tional lysosomes and regulate their constitutive transport as evident in abnormal secretion of kidney lysosomal to secretory lysosomes. Similarly, in neurons, two other enzymes in HPS mouse mutants (Swank et al., 1998). well-known lysosomal proteins and AP-3 cargoes, PI4KIIa However, the exact mechanism is unclear. In our and VAMP7-TI, are increased in synaptic vesicles (SVs; hypothesis, during lysosomal biogenesis, in concert with Newell-Litwa et al., 2009) but decreased in steady-state the expression of lysosomal proteins under the control of levels (Salazar et al., 2006) in either AP-3- or BLOC-1- TFEB, the lysosomal-trafficking HPS proteins are likely deficient neurons. When the sorting to lysosomes is involved in coordinating the transport and assembly of the disrupted, the cargoes may be missorted to SVs or vice lysosomal proteins into lysosomes. versa (Newell-Litwa et al., 2009). Lysosome-associated membrane proteins are known to function in the maintenance of lysosomal structures. HPS genes in the biogenesis of melanosomes The tetraspanin CD63 or LAMP3 is endocytosed and The study of melanosomal biogenesis provides an excel- directed to late endosomes and lysosomes where it lent example of LRO biogenesis (Marks and Seabra, functions as a constitutive lysosomal membrane protein. 2001; Raposo and Marks, 2002). PMEL is thought to be a AP-3 and BLOC-1 likely transport a cohort of lysosomal key molecule in melanosomal assembly (Theos et al., membrane proteins including CD63 into lysosomes. 2006). Other melanosomal components involved in mel- Accumulation of CD63 on the cell surface is seen in AP- anin synthesis include tyrosinase (TYR), OCA2, TYRP1, 3 or BLOC-1 knockdown cells, but with normal distribu- SLC45A2, SLC24A5, and DCT/TYRP2 and ATP7A (Ito and tion in BLOC-2 or BLOC-3 knockdown cells (Di Pietro Wakamatsu, 2011; Setty et al., 2008). How these mel- et al., 2006). The distribution of another LAMP protein, anosomal proteins are transported into melanosomes is LAMP1, is altered in a similar way (Salazar et al., 2006). beginning to be understood. PMEL is sorted into imma- Although missorted LAMPs are present on the plasma ture melanosomes, which is dependent on AP-2 (Robila membrane in AP-3- or BLOC-1-deficient cells, a majority et al., 2008) and CD63 (van Niel et al., 2011). TYR, OCA2, of these proteins are still present in bona fide lysosomes. and TYRP1 all contain acidic dileucine (LL)-based consen-

ª 2012 John Wiley & Sons A/S 183 Wei & Li sus motifs that can be recognized by AP-1, AP-2, or AP-3. requires additional study. As LROs exhibit tissue-specific Although DCT lacks the cytoplasmic LL-motif, it binds to compositions and functions, dissecting the cargo-specific AP complexes (Bonifacino and Traub, 2003), but how it is sorting mechanism is the first step to determine whether sorted into melanosomes is unknown. a cargo uses a pathway similar to that in melanosomal The HPACs have been known to mediate the transport biogenesis. The fact that BLOC-1 and AP-3 function of melanosomal proteins. These HPACs act as adaptors together seems to be more general in different cell types to cargo proteins during this transport as summarized in a such as neurons (Newell-Litwa et al., 2009), platelets recent review (Sitaram and Marks, 2012). TYR is sorted (Meng et al., 2012), and Hela cells (Borner et al., 2006). into the AP-3 buds of vacuolar endosomes, where TYR is Synaptic vesicles (SVs): In neurons, two synaptic directed into melanosomes via a BLOC-1-independent vesicle components, ZnT3 and VAMP2, are similarly pathway (Theos et al., 2005). BLOC-2 and RAB38 may sorted into SVs by the neuronal AP-3 isoform. However, act downstream of this AP-3-dependent pathway (Bulte- lysosomal transport mediated by the ubiquitously ma et al., 2012). In addition, a portion of TYR that is expressed AP-3 isoform and BLOC-1 complex functions sorted into AP-1 buds may compensate for its targeting to mainly in lysosomal targeting of AP-3 cargoes such as melanosomes when AP-3 is deficient (Theos et al., 2005). PI4KIIa and VAMP7-TI. When the ubiquitous AP-3 or In contrast, OCA2 is sorted into AP-1 or AP-3 buds and BLOC-1 is defective, cargoes that normally are sorted to thereafter is directed by BLOC-1 into mature melano- lysosomes are routed to SVs and vice versa (Newell- somes (Sitaram et al., 2009, 2012). Likewise, BLOC-2 Litwa et al., 2007, 2009; Salazar et al., 2009). A chloride and RAB38 act downstream of this BLOC-1-dependent channel, CIC-3, is packed in the synaptic-like microvesi- pathway (Bultema et al., 2012; Setty et al., 2007). How- cles (SLMVs) along with the ZnT3 mediated by AP-3 ever, TYRP1-sorting signals interact with AP-1 but not AP- (Salazar et al., 2004). In addition, loss of AP-3 results in 3 (Theos et al., 2005). Therefore, TYRP1 is sorted into increased synaptic vesicle size in the hippocampal den- mature melanosomes in a similar way as OCA2 via the tate gyrus, as opposed to decreased vesicle size in the BLOC-1-dependent pathway, but independent of AP-3 striatum. BLOC-1 likely contributes to these region- (Huizing et al., 2001b; Setty et al., 2007). Similar to specific effects of AP-3 (Newell-Litwa et al., 2010). TYRP1, the copper transporter, ATP7A, is sorted into Defects in synaptic vesicle size may lead to abnormal melanosomes via the BLOC-1-dependent pathway (Setty neurotransmission (Chen et al., 2008) and therefore the et al., 2008). development of abnormal behaviors as shown in dysbin- How other melanosomal proteins such as GPR143, din-null-mutant mice (Feng et al., 2008). How the HPS MART-1, and the other two transporters (SLC45A2 and genes regulate cargo transport in the biogenesis of SVs is SLC24A5) are sorted into melanosomes remains unclear. uncertain. On the other hand, although BLOC-3 has been described Large-dense core vesicles (LDCVs): The biogenesis of in regulating melanosomal biogenesis (Huizing et al., LDCVs in neuroendocrine cells is another good model to 2008; Li et al., 2004), its exact mechanism in melanos- study LRO biogenesis. Large-dense core vesicles bud omal protein trafficking is unknown. It has been sug- from the trans-Golgi network (TGN), and the aggregation gested that BLOC-3 acts as the RAB9 effector to regulate of granins drives their formation. The mature LDCV melanosomal biogenesis (Kloer et al., 2010). A recent release their contents (e.g., neuropeptides) under regu- study has shown that BLOC-3 acts as a RAB38/32 lated secretion. During LDCV biogenesis, sorting mech- guanine nucleotide exchange factor. BLOC-3 deficiency anisms are important to ensure proper cargo assembly results in mislocalization of RAB38 and RAB32 and into mature and condensed vesicles [reviewed by (Tooze reduction of pigmentation. It is suggested that proteolytic et al., 2001)]. AP-3 is likely involved in cargo sorting into maturation of PMEL and melanosomal biogenesis may be immature LDCVs. Lack of the ubiquitous AP-3 leads to a affected when this BLOC-3-/RAB38-dependent pathway dramatic increase of vesicle size and releasing quantal is disrupted (Gerondopoulos et al., 2012). It is unknown size (Grabner et al., 2006). In the absence of AP-3, LDCVs whether BLOC-3 itself acts as an adaptor for melanoso- contain less synaptagmin-1, CGA and SgII, which may mal protein trafficking. Finally, the HOPS complex may affect LDCV morphology (enlarged size and decreased function in the docking of AP-3-coated vesicles during number; Asensio et al., 2010). Similarly, the LDCVs in melanosomal biogenesis through the interaction between adrenal chromaffin cells of the dysbindin-null mutant mice VPS41 and AP3D (Angers and Merz, 2009; Rehling et al., are reduced in number and increased in vesicle size, 1999). leading to reduced secretion events and increased quan- tal size (Chen et al., 2008). The enlarged size of LDCV HPS genes in other non-melanosomal LROs might represent immature LDCVs. AP-3 or BLOC-1 may The biogenesis of melanosomes has provided important be involved in sorting LDCV cargoes into immature clues to understand the sorting mechanisms in the LDCVs or sorting unnecessary cargoes out of immature biogenesis of non-melanosomal LROs. However, LDCVs. Deficiency in AP-3 or BLOC-1 may block matu- whether the non-melanosomal LROs employ similar ration of LDCVs. Interestingly, it has been reported that cargo sorting mechanisms regulated by HPS genes chromaffin cells have two populations of LDCVs with

184 ª 2012 John Wiley & Sons A/S Hermansky–Pudlak syndrome distinct secretory properties, representing two distinct organelles is still a mystery. CD1B, but not other CD1 synthetic pathways for LDCV biogenesis or different isoforms, binds to AP-3. In AP-3-deficient cells, CD1B stages of biogenesis (Grabner et al., 2005). However, the fails to be targeted to lysosomes for antigen presentation. underlying mechanism of the biogenesis of these two The defects in CD1B antigen presentation may explain populations awaits further investigation. the recurrent bacterial infections in patients with HPS-2 Dense granules (DGs): During platelet activation, DGs (Sugita et al., 2002). In conventional dendritic cells (DCs), release small molecules like ATP, ADP, serotonin, and AP-3 efficiently recruits Toll-like receptor (TLR) to phago- calcium for blood clotting. The loss of DGs is regarded as somes and is involved in MHC-II presentation of antigens the gold standard in diagnosing HPS (Huizing et al., 2008). internalized by phagocytosis. In AP-3-deficient DCs, However, the underlying mechanism of DG biogenesis is export of the peptide: MHC-II complex to the cell surface not clear. SLC35D3 is a key component of DGs. Loss of was blocked (Mantegazza et al., 2012). AP-3, BLOC-1 and SLC35D3 causes lack of DGs in platelets (Chintala et al., BLOC-2 are essential for plasmacytoid dendritic cell 2007). A recent report has shown that SLC35D3 may signaling through TLR7 and TLR9 (Blasius et al., 2010; serve as either a cargo of DGs or a sorting molecule for Sasai et al., 2010). DG cargoes. Loss of BLOC-1 or AP-3 shows a reduction Lamellar bodies (LBs): Lamellar bodies in alveolar type of SLC35D3. However, SLC35D3 occurs at almost normal II (ATII) epithelial cells function in storage and secretion of levels in BLOC-3-deficient platelets. This suggests that surfactant which is important for lung function. LBs are BLOC-1 and AP-3 may function together in sorting abnormal in the Hps1/Hps2 double mutant. ATII cells and SLC35D3 into DGs (Meng et al., 2012). Other defects LBs of this mutant are greatly enlarged, and the LBs are of DG components are difficult to define as DGs are engorged with surfactant (Guttentag et al., 2005; Lyerla absent or empty in patients with HPS. KXD1 is a BLOC-1 et al., 2003). All these features are similar to the lung interactor. Kxd1 knockout mice exhibit reduced number pathology described in patients with HPS-1. This mutant of platelet DGs (Yang et al., 2012). This mouse mutant develops HPS-associated interstitial pneumonia (HPSIP) may offer a resource to uncover DG components defec- past 1 yr of age, which may be initiated by abnormal ATII tive in BLOC-1 inefficiency. cells and exacerbated by alveolar macrophage activation Weibel–Palade bodies (WPBs): WPBs are LROs spec- with elevated level of TGFb1 (Wang and Lyerla, 2010). ificly localized in endothelial cells. After stimulation, WPBs Likewise, the serum concentration of TGFb1 correlates quickly release their contents (such as von Willebrand with the severity of interstitial lung disease in patients factor (vWF), interleukin-8 (IL-8), P-selectin, and endo- with HPS-2 (Gochuico et al., 2012). Aberrant surfactant thelin) which play important roles in various physiological trafficking and secretion may lead to the apoptosis of ATII responses such as hemostasis, inflammation, angiogen- cells, thereby causing the development of HPSIP (Ma- esis, and wound healing. The involvement of HPS genes in havadi et al., 2010). In addition, the elevated TGFb1 may regulating WPB biogenesis has been reviewed (Metcalf trigger the activation of the epidermal growth factor et al., 2008). In this multi-step maturation model, two receptor (EGFR) pathway to develop lung fibrosis (Madala WPB components, P-selection and vWF, are sorted to the et al., 2011). On the other hand, HPS genes may down- immature WPB by AP-1 at the trans-Golgi network (TGN; regulate the EGFR signaling pathway by promoting Lui-Roberts et al., 2005). CD63 sorting to the mature WPB lysosomal degradation (Cai et al., 2010; Chirivino et al., is mediated by AP-3 (Harrison-Lavoie et al., 2006), while 2011). Inefficient lysosomal degradation due to the loss of Rab27A and Rab3D are further directed to the mature HPS proteins likely up-regulates the EGFR signaling to WPB by unknown mechanisms (Hannah et al., 2003; facilitate the development of lung fibrosis. Knop et al., 2004). Whether the BLOC complexes and Acrosomes: The acrosome is a member of the LRO HOPS complex are involved in WPB biogenesis is still family (Moreno and Alvarado, 2006; Raposo et al., 2007). unknown. Together with the defects in platelet DG, Similarly to other LROs, it undergoes a multi-step matu- defects in the WPB biogenesis may contribute to the ration process (Berruti and Paiardi, 2011). Cargoes are bleeding tendency observed in patients with HPS. packaged into the pro-acrosomal granule (PG) from TGN Cytolytic granules (CGs): HPS genes may also regulate and early endosomes. VPS54, a member of the Golgi the biogenesis of CGs in cytotoxic T lymphocytes (CTLs) associated retrograde protein complex, is likely involved and NK cells. In patients lacking AP-3, granule polarization in sorting cargoes from endosomes. The Vps54 mouse is defective, thus CTL secretion is severely impaired mutant, wobbler, lacks acrosomes and is infertile (Paiardi (Clark et al., 2003). In mouse mutants deficient in Rab27a et al., 2011). By sorting-in and sorting-out mechanisms, and Rabggta, CTL secretion is also impaired (Stinch- PG is converted to pro-acrosome (PA) and the latter turns combe et al., 2001). However, the CGs may not be to be a mature acrosome. AP complexes, ESCRT com- affected in CTLs deficient in BLOC-1, BLOC-2, BLOC-3, plexes and motor proteins are likely involved in the and HOPS (Bossi et al., 2005). acrosome biogenesis. Acrosomal defects have not been MHC-II compartments: MHC-II compartments in anti- described yet in any of the HPS mouse mutants. gen-presenting cells undergo a process of maturation Other LROs: The pallid, muted, and mocha mice show during antigen presentation. The biogenesis of these absence of or abnormality in otoliths of the inner ear and

ª 2012 John Wiley & Sons A/S 185 Wei & Li reduced inner ear pigmentation, suggesting that HPS exploration of phenotypes in HPS, other LRO defects genes are involved in both otolith biogenesis and melano- would be expected in a tissue-specific manner. some biogenesis in inner ear (Swank et al., 1991). How- ever, the underlying mechanisms for otolith defects of HPS genes in modulating signal these mouse mutants are unknown. The otic vesicle (OV) transduction is likely another kind of LRO. Nascent otoliths are formed from a pool of precursor particles and tethered to cilia in the Lysosomes function in the degradation of endocytosed OV (Riley et al., 1997). Thus, OVs and cilia play important ligands or receptors in order to turn off signal transduction roles in otolith biogenesis. Manganese supplementation in in a proteosome-independent pathway. In HPS, when pallid mice rescues the otolith defect but not hypopigmen- lysosomal degradation is impaired, the targeted receptors tation (Erway et al., 1971). In addition, transportation of (such as dopamine receptor D2R, glutamate receptor manganese is delayed in pallid tissues (Cotzias et al., NR2A) are often reinserted into the plasma membrane to 1972). These results suggest that the otolith defects in increase their number (Ji et al., 2009; Tang et al., 2009b). these HPS mutants may be due to a defect in the trafficking Similarly in plants, we have shown that the deficiency in of a manganese transporter or an unknown protein for BLOC-1 leads to increase of plasma membrane expres- which activity manganese is required in OVs. sion of auxin effluxers PIN1 and PIN2, to up-regulate the Vps33a mutant mice (buff) show defects of uroplakin- auxin response and facilitate root development in Arabid- delivering fusiform vesicles in urothelial umbrella cells. opsis (Cui et al., 2010). However, deficiency of the AP-3 b These vesicles were almost completely replaced by subunit leads to the intracellular ectopic accumulation of Rab27b-negative multivesicular bodies in mutant mice PIN1 protein, causing root growth arrest of seedlings (Guo et al., 2009). In addition, mutation of Vps33a affects when growing in medium lacking sucrose (Feraru et al., the cell surface expression level of RANKL and disrupts the 2010). The opposite phenotypes of BLOC-1 and AP-3 in trafficking of RANKL to the secretory lysosomes in osteo- Arabidopsis suggest that these two complexes may act blasts or bone marrow stromal cells (Kariya et al., 2009). differently in the recycling and degradation of PIN Pancreatic islet beta-cells contain SLMVs. The sedimen- proteins. AP-3, HOPS, BLOC-1, and BLOC-2 have been tation properties of beta-cell SLMVs are identical to those involved in modulating signal transduction. The known from PC12 cells. Neuronal AP-3b subunits are expressed in effects on receptor trafficking in HPS are summarized in beta-cells. Inhibition of AP-3 prohibits the delivery of AP-3 Table 4. Impaired signaling affects multiple cellular func- cargoes to beta-cell SLMVs, suggesting that beta-cells tions, such as neurotransmission, cell proliferation or share mechanisms for mediating the neuron-specific syn- differentiation, innate immune response, and organ aptic vesicle formation (Suckow et al., 2010). With the development. We are at the beginning stages of estab-

Table 4. Abnormal receptor trafficking in HPS

Receptors BLOC-1 BLOC-2 AP-3 HOPS

D2R Increased on cell surface (Ji et al., 2009) Deltex/Notch Sort to lysosomal limiting Sort to lysosomal limiting receptor membrane (Wilkin et al., 2008) membrane (Wilkin et al., 2008) EGFR Delayed degradation Accumulation in endosomes (Cai et al., 2010) and delayed degradation (Chirivino et al., 2011) MR5 Decrease in the magnitude of presynaptic M5-mediated dopamine release potentiation in the striatum (Bendor et al., 2010) NR2A Increase on cell surface (Tang et al., 2009b) TLRs Impaired TLR7/9 Impaired TLR7/9 trafficking Impaired TLR7/9 trafficking and trafficking and type and type I IFN production type I IFN production (Blasius et al., IIFN production (Blasius et al., 2010) 2010; Sasai et al., 2010). (Blasius et al., 2010) Impaired CD4(+) T cell activation and Th1 effector cell function (Mantegazza et al., 2012)

D2R, dopamine receptor 2; EGFR, epidermal growth factor receptor; MR5, M(5) muscarinic acetylcholine receptor; NR2A, NMDA receptor 2A; TLR, Toll-like receptor; IFN, interferon; HPS, Hermansky–Pudlak syndrome.

186 ª 2012 John Wiley & Sons A/S Hermansky–Pudlak syndrome lishing a link between lysosomal-trafficking and signal References modulation. Modulation of signal transduction by HPS genes opens new avenues to study the mechanisms Ambrosio, A.L., Boyle, J.A., and Di Pietro, S.M. (2012). Mechanism of platelet dense granule biogenesis: study of cargo transport and underlying developmental abnormalities, disrupted neu- function of Rab32 and Rab38 in a model system. Blood 120, 4072– rotransmission, and metabolic dysfunction. 4081. Anant, J.S., Desnoyers, L., Machius, M., Demeler, B., Hansen, J.C., Perspectives and conclusions Westover, K.D., Deisenhofer, J., and Seabra, M.C. (1998). Mech- anism of Rab geranylgeranylation: formation of the catalytic ternary During autophagy and phagocytosis, the formation of complex. Biochemistry 37, 12559–12568. autolysosomes and phagolysosomes is a crucial func- Anderson, P.D., Huizing, M., Claassen, D.A., White, J., and Gahl, W. A. (2003). 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Boissy, R.E., Richmond, B., Huizing, M., Helip-Wooley, A., Zhao, Y., This work was partially supported by grants from National Natural Koshoffer, A., and Gahl, W.A. (2005). Melanocyte-specific proteins Science Foundation of China (31230046, 81101182), from Chinese are aberrantly trafficked in melanocytes of Hermansky–Pudlak Academy of Sciences (KSCX2-EW-R-05) and from The State Key syndrome-type 3. Am. J. Pathol. 166, 231–240. Laboratory of Molecular Developmental Biology, China. We are very Bonifacino, J.S., and Traub, L.M. (2003). Signals for sorting of thankful to Dr. Richard T. Swank for his reading of this manuscript transmembrane proteins to endosomes and lysosomes. Annu. and critical comments. We apologize to the authors of relevant works Rev. Biochem. 72, 395–447. that are not mentioned in this review.

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