The Coronin Family and Human Disease

Send Orders for Reprints to [email protected] Current Protein and Peptide Science, 2016, 17, 000-000 1 The Coronin Family and Human Disease

Xiaolong Liua,*, Yunzhen Gaoa, Xiao Linb, Lin Lia,b, Xiao Hanc and Jingfeng Liua,b aThe United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China; bThe First Affiliated Hospital of Fujian Medical University, Fuzhou 350007, People’s Republic c of China; Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing Please provide corresponding author(s) 100081, People’s Republic of China photograph size should be 4" x 4" inches Abstract: The Coronin family is one of the WD-repeat domain containing families that are diverse in both of their structures and functions. The first coronin was identified in the cytoskeleton composition of Dictyostelium discoideum, which was discovered to regulate the actin functions. So far, 723 coronins have been identified throughout the eukaryotic kingdom by bioinformatics analysis in 358 species. In mammals, 7 coronins have been identified to date, which are named through Coronin 1 to Coronin 7; all of these isoforms contain two structurally conservational region: a 7-bladed β-propeller scaffold in N-terminal and a C-terminal variable coiled coil domain. Although some studies were showing that mammalian coronins have regulated the actin dynamics, recently many other functions such as calcium signaling regulation, cAMP signaling regulation, have been also reported beyond the actin modulation. Furthermore, many diseases have been found to be extensively associated with the abnormal expression of coronins, such as auto-immunity, bacterial and virus infection, neuronal behavior disorder and cancer. In this review, we would like to systematically discuss the recent progresses of mammalian coronins and associated diseases, as well as possible underlying molecular mechanisms. Keywords: Coronin, human disease, cAMP signaling, cancer, WD repeats, actin associated protein

1. INTRODUCTION (1C); the type II class is including Coronin 4 (2A), Coronin 5 (2B) and Coronin 6; the type III class is only including The first coronin was identified through co-purifying Coronin 7 [4-6]. with F-actin at the crown-like structures on the dorsal surface of slime mold Dictyostelium discoideum by Hostos and col- According to the molecular signature, the coronins are leagues in 1991 [1, 2]. Afterwards, 723 coronins have been highly conserved WD-repeat domain containing proteins identified throughout the eukaryotic kingdom except in over roughly 800 million years of eukaryotic evolution [2, plants or distant protists by bioinformatics analysis in 358 9]. Coronins comprise three domains, a N-terminal of WD40 species [3]. repeats containing domain, a linker domain consisting of a C-terminal extension and an unique region at the C-terminal. In Dictyostelium discoideum, three coronin like proteins For some members of the family, there are a coiled coil have been identified, coronin or corA which is a short structure in the C-terminal. The coronins have seven WD40 coronin, Coronin7 (corB) and villidin which are belonging to repeats (seven bladed β propellers) assembled from five ca- the long coronins [4]. Unlike Dictyostelium discoideum, the nonical WD repeats and two noncanonical repeats in N- yeast only has a single coronin protein, termed as crn1 [5]. terminal domain (interact with actin or (and) membrane). But, there are ten coronin proteins in Danio retio (zebrafish) Following the WD motif is the C-terminal extension and [6]. unique region that differs in length and sequence among In mammals, there are 7 coronins were characterized to members of the family with poorly understood functions [7, date, and two synonymous names are used for the mammal- 10]. The coiled coil domain is the smallest functional region ian coronin family members. The mammalian coronin family of coronins and contribute to at least three different func- is including Coronin 1 (Coronin 1A), Coronin 2 (Coronin tional interactions: directly binding to actin, directly interact- 1B), Coronin 3 (Coronin 1C), Coronin 4 (Coronin 2A), ing with the Arp2/3 complex and the homo-oligomerization Coronin 5 (Coronin 2B), Coronin 6, and Coronin 7 [7, 8]. which is required for actin filaments bundling by coronin The mammalian coronins could be subdivided into three [11]. In mammals, all from Coronin 1 to Coronin 6 exhibit classes based on their sequence similarity; the type I class is the classical coronin structures, but Coronin 7, the longest including Coronin 1 (1A), Coronin 2 (1B), and Coronin 3 mammal coronin, lacks the coiled coil domain [12-14].

Coronins are expressed in distinct patterns across cell *Address correspondence to this author at the Xihong Road 312, Fuzhou types and tissues in mammalian, and the alternative splicing 350025, Fujian Province, P.R. China; Tel.: +86591-83705927; of the mRNA increases the differences of expression patterns E-mail: [email protected] among the vertebrate (Table 1). Coronin 1, having 2 iso-

Fig. (1). The structural domains and phylogenetic relationships of mammalian coronins. The phylogenetic tree (left) indicates that mammalian coronins could group into three classes. Seven human coronins have the same basic structure (right): an N-terminal extension (NE), a seven-bladed β-propeller, a C-terminal extension (CE) and an unique region (U). Type I and Type II coronins have a C-terminal coiled coil domain (CC), whereas the Type III coronin lacks this region but instead contains two tandem coronin repeats.

Table 1. Summary of mammalian coronins.

Subtype HGNC name Aliase Isoform: Protein Related Expression pattern Ref mRNA/protein length(aa) disease

1 Coronin 1A Coronin1; p57; 2/1 461 SCID; Hematopoietic cells [7, 11, IMD8; TACO; SLE; and tissues; Neuronal 34-45] CLABP; HCORO1; MS; Pathogenic tissues Clipin A infection

Coronin 1B Coronin 2 2/1 489 Ubiquitously [12, 16]

Coronin 1C Coronin 3; 3/2 527/474 Diffuse Gliomas; Ubiquitously [16, 60, HCRNN4 HCC; 62-64, Gastric Cancer; 66-70] Lung Cancer

2 Coronin 2A Coronin 4; IR10; 2/1 525 Inflammatory Testes; [7, 75] Clipin B; WDR2 Ovary; Uterus; Brain

Coronin 2B Coronin 5; Clipin C 3/2 480/475 Ubiquitously with [14] high in brain

Coronin 6 Coronin 6 1/1 472 CMS Ubiquitously with [7, 78, high in brain 79, 83]

3 Coronin 7 POD; CRN7 3/3 925/907/ 840 Obesity Ubiquitously [7, 13, 87]

forms that encode the same protein, is mainly expressed in sues [12, 14]. Coronin 7, the vertebrate homolog of the hematopoietic cells and tissues with a low expression level in Caenorhabditis elegans gene POD, is expressed ubiquitously neuronal tissues [15]. Coronin 2 is ubiquitously expressed in but with low levels in heart, lung and muscle, and is alterna- most tissue with two mRNA isoforms that encode the same tively splicing into 3 isoforms [13, 18]. protein [16]. Coronin 3 the most ubiquitously expressed The functions of mammalian coronins are still not clearly coronin with 3 isoforms [17]. Coronin 4 is only expressed in unrevealed, especially in the coronins associated diseases. In testes, ovary, uterus and brain [12, 14]. Coronin 5 only pre- this review, we would like to discuss the recent key studies sents in the genome with little information in EST (expressed related to the coronins, and attempt to integrate the current sequence tag) database. Coronin 6, which has two isoforms, understanding of the functions of coronins into human dis- is enriched in brain with low expression levels in other tis- ease. The Coronin Family and Human Disease Current Protein and Peptide Science, 2016, Vol. 17, No. ?? 3

2. CORONIN 1 such an activity is involved in pathogen survival in macrophages and / or T cell homeostasis [20, 29-34]. Coronin 1 (HGNC name: Coronin 1A, HGNC symbol: CORO 1A) is one of the best characterized mammalian 2.1. Coronin 1 Is Involved in the Diseases of Immune Sys- coronins and is highly expressed in cells of hematopoietic tem lineage and in neuronal tissues, where it localizes at the cell cortex [2, 19-22]. Originally, it was known as P57 associated The Coronin 1 is abundantly expressed in T cells, B cells, with phosphoinositol-specific phospholipase (PI-PL) C, and dendritic cells, macrophages, mast cells, neutrophils and was also studied as TACO (Tryptophan Aspartate containing neurons [21, 35], and it has been reported to be important for Coat protein) which is located around the mycobacteria- the functions of immune system. Mismatch function of containing phagosomes. With the better understanding of the Coronin 1 causes diverse of diseases in immune system in- mouse and human genomes, the P57 or TACO as well as cluding severe combined immunodeficiency (SCID) which is several homologous molecules were identified to belong to a characterized by profound block in T cells, partially with B member of protein family called coronins that were con- and NK cells defects [36]. Coronin 1 deficient patient served from yeast to human, and it was then referred as showed profound naïve T cell lymphopenia identified by coronin 1 [19] (Table 1). Structurally, Coronin 1 has three drastically reduced CD3+CD4+CD45RA+ and domains, a N-terminal (WD repeat-containing β-propeller), a CD3+CD8+CD45RA+ cells, but had intact thymus [37-40]. linker domain with coiled coil motif and an unique domain at This evidence indicates Coronin 1 is required to provide pro- the C-terminal [9]. The WD domain contains 7 bladed β- survival signals of CD4 as well as CD8 positive T cells. Fur- propeller which interacts with actin or (and) membrane. Bio- thermore, Coronin 1 is also an important modulator of auto- physical and structural analysis demonstrated that the C- immunity disease. Haraldsson et al. searched for genetic loci terminal 30–40 residues of Coronin 1 fold into a parallel associated with autoimmunity disease (systemic lupus three-stranded and an α-helical coiled coil domain that medi- erythematosus, SLE) and found that a nonsense mutation in ated trimerization of Coronin 1 molecules [11]. Although the the Coronin 1 gene could suppress lupus [41]. In parallel role of the C-terminal coiled coil domain in Coronin 1 with SLE, multiple sclerosis (MS) is another auto immune trimerization is well established, the importance of trimeriza- disease of human with inflammatory cells infiltrating into tion for the biological activity of Coronin 1 remains unclear. central nervous system. Coronin 1 positive T cells and In macrophages, it has been reported that the C-terminal macrophages were found in active MS lesions in the brain coiled coil domain was improtant for its subcellular localiza- samples from MS patients analyzed by immunohistochemis- tion at the cell cortex [23]. try [42]. The similarity of Coronin 1 with the actin-binding coron- The role of Coronin 1 in the diseases of immune system ins in Dictyostelium discoideum and yeast led to an initial suggested that it could be a novel therapeutic target. Further focus on its cytoskeleton regulation functions. It has been studies revealed that antibodies reactive to the peptide UH- reported that Coronin 1 participated in lamellipodial archi- CIS6 in the cerebrospinal fluid of MS patient could recog- tecture and dynamics via regulating F-actin bundling process nize the Coronin 1 protein [43]. Furthermore, a novel mono- through directly binding to the Arp2/3 complex by its coiled clonal antibody named ACH-2B8a (2B8a) could target coil domain and the C-terminal unique domain, thus lead to Coronin 1 that was strictly expressed on lymph tissues and the inhibition of the nucleation of actin. Meanwhile, it has hematopoietic cells [44]. Once binding to the antigen on the also been reported that Coronin 1 could activate the cofilin targets cells, antibody 2B8a was quickly internalized into which worked together with Arp2/3 complex to depolymeri- target cells and was capable of killing tumor cells through zation F-actin [24]. Furthermore, some other functions rather complement dependent cytotoxicity [44]. than actin modulation have also been reported such as cal- Recently, highly expressed Coronin 1 was also found in cium signaling regulation and cAMP signaling regulation. T cells from hemophagocytic lymphohistiocytosis and aplas- The function of Coronin 1 in mammals was initially dis- tic anemia patients, which indicate that Coronin 1 also plays covered through the analysis of the immune evasion mecha- important roles for T-lineage malignancies and immune dis- nisms of Mycobacterium tuberculosis. Coronin 1 was firstly orders mediated by activated T cells [45]. identified as a host factor that protected the lysosomal delivery of pathogenic mycobacteria in resting macrophages [25]. 2.2. Coronin 1 Participates in Cognition and Behavior Subsequent work revealed that mice were virtually devoid of Beyond the immune system, Coronin 1 deficiency was naïve T cells in the absence of Coronin 1 [26-29]. It sug- also identified in humans with neurocognitive and behavioral gested an essential role of Coronin 1 in T cell homeostasis abnormal including aggression, poor memory formation and which are important for maintaining T cells in the periphery. This role was found to be a result of activating the defective in social interactions [31, 32]. Studies from mice models have shown that Coronin 1 gene knockout mice Ca2+/calcineurin pathway following T cell receptor trigger- showed a significantly enhanced aggressive behavior, en- ing by Coronin 1. Interestingly, activating the hanced grooming, lowered anxiety, and defective in memory Ca2+/calcineurin pathway led to sustain Mycobacteria sur- formation compared with the wild-type mice [31]; further vival within macrophages [30]. More recently, neuronal ex- analysis indicates that the abnormal behaviors of Coronin 1 pressed Coronin 1, as well as its homologue in the lower eukaryote Dictyostelium discoideum, have been implicated to deficient mice were due to the defects in the cAMP / protein kinase A (PKA) signaling pathway modulated by interac- play functions in the activation of the cAMP/protein kinase tions between Coronin 1 and G protein subtype Gαs [31]. A pathway. However, it’s remained to be established that 4 Current Protein and Peptide Science, 2016, Vol. 17, No. ?? Stefano Costanzi

2.3. Coronin 1 in the Pathogenic Bacterial Infection ies are required to establish the association of Coronin 2 with relative diseases in humans. To combat with bacterial infection, phagosomes are formed by phagocytosis when the macrophage engulfs bacte- 4. CORONIN 3 ria. Then the membrane of the phagosomes is fused with lysosomes to destroy the bacteria [46]. The fusion of the Coronin 3 (HGNC name: Coronin 1C, HGNC symbol: membrane was mediated by the nucleation of actin filaments CORO 1C), a short protein of 474 aa is the most widely ex- around nascent phagosomes [47]. Coronin 1 also has been pressed coronin protein in mammals and localizes to lamel- reported to play very important roles during this process lipodia [8, 57] (Table 1). It was discovered in the early of [20]. It has been reported that bacterial protein lipoamide nineties as the gene mig-3 (mitogen induced gene 3). Later in dehydrogenase C (LpdC) could act as a Coronin 1 binding 2004, Coronin 3 was independently identified as a serum- protein to recruit and retain the Coronin 1 on the phagosome induced gene in fibroblasts [58, 59]. Coronin 3 is a type I [48]; using this mechanism, pathogenic bacteria such as My- coronin protein which is part of a conserved family of WD- cobacterium tuberculosis can retain Coronin 1 (TACO) on repeat containing, actin-binding proteins. The roles of the phagosome surface, thereby preventing the fusion of Coronin 3 in human diseases are suggested by recent studies. phagosomes with lysosomes [20]; the trimerization of It has been reported that Coronin 3 could interact with Coronin 1 mediated by serine phosphorylation is essential Arp2/3 and negative regulate actin polymerization [60]; in for its activity to promote Mycobacteria survival [23]. Taken addition, Coronin 3 could negatively regulate cell motility together, these data suggest that Coronin 1 might be promis- through modulation of cell-matrix adhesion via Focal Adhe- ing therapeutic target for pathogenic bacteria infections. sion Kinase [61]. These evidences strongly suggest that Coronin 3 may be involved in the human diseases such as 3. CORONIN 2 metastasis of cancer [29]. Coronin 2 (HGNC name: Coronin 1B, HGNC symbol: 4.1. Coronin 3 Promotes the Malignant Phenotype of CORO 1B) was fisrt identified as a phosphoprotein in HCL- Human Diffuse Gliomas secreting gastric parietal cells of rabbit [2, 49, 50] (Table 1). The mouse Coronin 2 with an unique short C-terminal region Using histopathological analysis and immunoblot, Dr. is different from rabbit coronin. Coronin 2 is ubiquitously Thal et al. [62] analyzed the expression pattern of Coronin 3 expressed and is primarily localized to cortical F-actin struc- in normal human brain and in brain tumors. In the normal tures in the kidney [51]. It is localized to early phagosomes adult human brain tissue, Coronin 3 has certain expression in with a perinuclear punctate pattern in subcellular level [52]. neurons of the cortex, while it is absent in the white mater. Coronin 2 can be phosphorylated by PKC on serine which However, the expression pattern of the Coronin 3 was tumor led to a partial redistribution of Coronin 2 to the leading edge type dependent in brain tumors. Coronin 3 is strongly ex- of the induced actin-rich filopodia. Phosphorylated Coronin pressed in benign meningiomas, pilocytic astrocytomas, 2 was inactive; the WISp39 (Waf1 Cil1 stabilizing protein high-grade oligodendrogliomas, oligoastrocytomas, anaplas- 39) could form complex with SSH (Slingshot phosphatase) tic astrocytomas and glioblastomas; while only very weak to dephosphorylate and activate Coronin 2, then coordinate Coronin 3 staining was observed in the tumor cells of low- the activation of cofilin and regulation the binding with grade diffuse astrocytomas, oligodendrogliomas and oligoas- Arp2/3 complex at the leading edge [53].Wt1 (Wilms’tumor- trocytomas. Furthermore, the desmoplastic medulloblas- 1), a zinc finger transcription factor which plays a crucial tomas and neuroblastoma, two benign tumor entities, had no role in the normal development of the organs including kid- detectable expression of Coronin 3. Within mixed gliomas, ney, spleen, lung and heart, was identified to bind with GC- Coronin 3 had higher expression levels in astroglial tumor rich region of the Coronin 2 promoter to regulate the cells than those of the oligodendroglial components. Mean- Coronin 2 gene expression [53-56]. while, the expression of Coronin 3 within an individual tumor was variable. Almost all tumor cells in glioblastomas Although, there is no report on the association of Coronin expressed Coronin 3, while tumor cells adjacent to proliferat- 2 with human diseases, studies within different cell lines ing microvessels in the tumor periphery were shown signifi- indicated the role of Coronin 2 in vascular lesion formation cant stronger Coronin 3 expression than that of adjacent to and cell chemotaxis [54, 55]. Platelet-derived growth factor (PDGF) induced vascular smooth muscle cell (VSMC) mi- necrosis areas. Coronin 3 also expressed in the reactive as- trocytes, non-malignant but activated and migrating cells in gration is an important step in vascular lesion formation. the matrix of brain tumors. This phenomenon was also hap- Down-regulation of Coronin 2 in VSMC mediated the mi- pened in other brain lesions like infarcts and traumatic le- gration induced by PGDF through increasing the lamellipo- sions. In contrast, non-specific astroglial activation cells dia protraction rate and protrusion distance [54]. In another showed only faint expression of Coronin 3. way, Coronin 2 is required for sphingosine-1-phosphate (S1P)-induced chemotaxis in human pulmonary artery endo- There is a strong relationship between the expression thelial cells (HPAECs). The down regulation of Coronin 2 level of Coronin 3 and the malignance of diffuse gliomas by siRNA could significantly induce chemotaxis of HAPECs [63]. Expression level of Coronin 3 was positive associated [55]. In an experimental spinal cord injury system, Coronin with the degree of malignancy of the diffuse gliomas such as 2, RAb13 (Ras-related protein Rab-13) and GAP-43 (growth astrocytomas, oligodendrogliomas and oligoastrocytomas. associated protein-43, Neruomodulin) were co-expressed The relationship between Coronin 3 expression and the mi- during the recovery of the nerve [56], which indicates that gration of tumor cells was tested in U373 and A172 glioblas- Coronin 2 are required for nerve regeneration. Further stud- toma cell lines by shRNA-mediated knockdown of Coronin The Coronin Family and Human Disease Current Protein and Peptide Science, 2016, Vol. 17, No. ?? 5

3. Knockdown of Coronin 3 significantly hampered cell pro- ship between Coronin 3 expression and clinicopathological liferation rate, cell migration velocity, formation of invado- parameters was also analyzed. The high expression level of podia, secretion of matrix metalloproteinases and invasion Coronin 3 is associated with the increased clinical stage and ability. The extent of migration and invasion of tumor cells lymph lode metastasis, but not associated with cancer differ- into health tissue was an important factor that limits the suc- entiation, or patient’s gender and age [70]. As shown by the cess of surgery of diffuse gliomas [63]. These results demon- result of tissue array containing 40 gastric cancer and related strated the contribution of Coronin 3 in the malignant pro- lymph lodes, Coronin 3 was predominantly expressed in the gression of diffuse gliomas. cytoplasm and metastatic lymph lode samples. To investigate the role of Coronin 3 in gastric cancer, Coronin 3 was 4.2. Coronin 3 Involves in the Progression of Hepatocel- knockdown and overexpressed by a lentivirus vector contain- lular Carcinoma (HCC) ing a shRNA construct and pcDNA3.1-Coronin 3 construct, respectively. The down-regulation or up-regulation of To identify potential membrane protein related to HCC Coronin 3 had no detectable effects on cell growth, apoptosis invasion, Wu et al performed proteomic analysis, experimen- or cell cycle progression of gastric cancer cells. But the tal animal studies and clinical validation using human HCC down-regulation of Coronin 3 strongly inhibited the migra- cell lines with different metastasis potentials [64], HCCLM9 tion and invasion ability of MKN45 cells. In contrast, the up- (high metastasis capacity) and MHCC97L (low metastasis regulation of Coronin3 significantly enhanced the migration capacity). The proteomic and western blot analysis data and invasion of MKN28-N cells. This phenomenon was also clearly indicated that the expression levels of Coronin 3 in confirmed by vivo metastasis assay in nude mice. HCCLM9 was significantly higher than that of MHCC97L. This was further confirmed by immunohistochemically stain- Furthermore, many molecules involved in the gastric ing of Coronin 3 in nude mice model of HCC. The high ex- cancers such as MMP-9 and CTSK (cathepsin K) were iden- pression of Coronin 3 was strongly related with tumor spon- tified as the downstream of Coronin 3 [71]. Coronin 3 could taneous pulmonary metastasis in nude mice model of HCC. significantly promote the expression of MMP-9 and CTSK Furthermore, Wang et al overexpressed and knockdown of in gastric cancer; proteases such as MMPs could degrade Coronin 3 in HCC cell line BEL-7402 to test the function of basement membrane and extracellular matrix (ECM) which Coronin 3 in the cell migration, invasion and proliferation was the initial step of metastasis process [70, 71]. Thus, in- [65]. Their data indicated that Coronin 3 could enhance cell creased expression of MMP-9 and CTSK may partially con- motility and proliferation. Knockdown of Coronin 3 in the tribute to the functions of Coronin 3 in the gastric cancer BEL-7402 cells could reduce the stress fiber network and metastasis. decrease lamellipodial extension, then attenuate the malignant potential of BEl-7402 cells in mice model [65]. In clini- 4.4. Coronin 3 Inhibites Cancer Cell Proliferation, Mi- cal HCC tissues, Coronin 3 was significantly different ex- gration and Invasion in Lung Cancer pressed among HCC specimens of different clinical stages. Analyzing microRNA (miRNA) expression signatures of Compared with early stage (Barcelona Clinic Liver Cancer I lung squamous cell carcinoma (SCC), Mataki et al. revealed and II), the later stage (Barcelona Clinic Liver Cancer III and that miR-1/133a cluster were significantly reduced in SCC IV) had significantly stronger stain of Coronin 3 (28.6% and cancer tissues [72]; meanwhile, the miR-1/133a cluster is 46.7%, respectively) [64]. significantly reduced in several other types of cancer includ- Recently, it has been reported that Coronin 3 was associ- ing prostate cancer, head and neck cancer, and urothelial ated with another key factor Rac-1 in hepatocellular carci- carcinoma [73, 74] as well. Restoration of both matured noma, a Rho family small GTPase, participating in many miR-1 and miR-133a could significantly inhibit cell prolif- activities of cells including cell cytoskeletal reorganization, eration, migration and invasion of EBC-1 cells. Gene expres- cell growth, cell migration and invasion [66]. Rac1 could sion data and in silico database analysis indicated that translocate from the cytosol to the membrane and then re- Coronin 3 was a common target gene of the miR-1/133a lease from its inhibitor RhoGDI to become activated [67]. cluster, and this was confirmed by the luciferase reporter Rac1 activation was related with the migration of tumor cells assay. Loss-of-function assay showed that silencing Coronin and tumor metastasis in HCC [68]. Although the overexpres- 3 inhibited lung cancer cell proliferation, migration and invasion or knockdown of Coronin 3 did not alter the expression sion. Furthermore, a total of 967 genes were identified as of Rac1 protein, Coronin 3 could enhance Rac1 activation by being down-regulated in Coronin 3 silenced lung cancer cells triggering the interaction between GTP and Rac1, and there- compared with the control by genome-wide gene expression fore enhance the metastasis by promoting a more rapid actin analysis; and a total of 29 pathways were identified as being dynamics [65]. All those data indicated that Coronin 3 might regulated by Coronin 3 according to KEGG pathway analy- be used as a prognostic biomarker for the HCC malignancy. sis. These data suggest that Coronin 3 might play important roles in the metastasis of lung squamous cell carcinoma and 4.3. Coronin 3 Is Associated with the Invasion of Gastric might be potential therapeutic target [72]. Cancer 5. CORONIN 4 Coronin 3 expression has also been examined in gastric cancer tissues and cell lines, as well as in the related lymph Coronin 4 (HGNC name: Coronin 2A, HGNC symbol: lodes in primary gastric cancer [69]. It has been reported that CORO 2A), a member of type II coronin protein family, was the Coronin 3 expression was detected in 152 gastric cancer identified as a component of the nuclear receptor corepressor tissues by immunohistochemistry; meanwhile, the relation- (NCoR) complex in Hela cells (Table 1). The N-terminal and 6 Current Protein and Peptide Science, 2016, Vol. 17, No. ?? Stefano Costanzi the WD-40 repeats domain of Coronin 4 interact with the ters [81]. These evidences indicate that Coronin 6 might play RD1 and RD4 motif of NCoR, respectively [75]. In contrast important roles in the congenital myasthenic syndrome. with type I coronin family members, Coronin 4 is localized to stress fibers and some focal adhesions in MTLn3 cells 8. CORONIN 7 which is function as a regulator for a subset of focal- adhesion-turnover events [76]. In BMDMs (primary bone Coronin 7 (HGNC name: Coronin 7, HGNC symbol: CORO 7) was first identified in a screen aimed to isolate marrow-derived macrophages), the Coronin 4 is primarily C.elegans actin binding proteins (named CABP11) and it co- localized to the nucleus where it is co-localized with NCoR localized with cortical actin at the membranes of cell organ- [77]. This co-localization with NCoR bring the Coronin 4 elle to facilitate vesicular trafficking (Table 1). Human binding to the promoter of NCoR target genes such as Nos2 Coronin 7, which contains 925 amino acids and belongs to and Ccl2 in resting macrophages, and such binding could be reduced through activating macrophages by TLR4 ligand the type III coronin, displays 29% and 30% identical to C.elegans Coronin 7 (POD-1) and Drosophila Coronin7 lipopolysaccharide (LPS) [77]. (Dpod-1); meanwhile, it displays 47% and 46% homologous Inflammatory response is a key step in control the ho- to C.elegans Coronin 7 (POD-1) and Drosophila Coronin7 meostasis of immunity. Toll-like receptors (TLRs) is an ini- (Dpod-1), respectively. Unlike other coronins in human, tiator of inflammation through sense pathogen-associated Coronin 7 had two WD repeats [2, 8, 18, 85]. molecular patterns [78, 79]. Coronin 4, as a component of Human Coronin 7 was significantly expressed on the the NCoR complex, mediates TLR-induced NCoR turnover vesicle-like cytoplasmic structures and on the cis-Golgi, through interaction with oligomeric nuclear actin [77]. The while predominantly negative expressed on the trans-Golgi role of Coronin 4 on suppression of the expression of in- [13]. However, Coronin 7 could target to trans-Golgi de- flammatory response genes provides new target for control- pending on the interaction with Eps15 through cullin 3 ling the homeostasis of immunity, but further information is still needed to establish the relations between Coronin 4 and (Cul3) and its substrate adaptor KLHL20 (ubiquitin E3 ligase) which catalyzed a K33-linked, nondegradable polyu- certain disorders of humans. biquitination on Coronin 7 [86]. This interaction chain could stabilize the F-actin assemble of trans-Gogli pool, which is 6. CORONIN 5 an essential process for generating transport carriers. Knock- Coronin 5(HGNC name: Coronin 2B, HGNC symbol: down of Coronin 7 is resulting in Golgi breakdown and ac- CORO 2B), also known as Clipin C (coronin-like protein C), cumulation of arrested cargo proteins [87]. was first identified by Nakamura et al. in 1999 (Table 1). Obesity is a growing global concern because it is associ- Coronin 5 has similar structure with other coronins and be- ated with cardiovascular disease, type-2 diabetes and cancer. longs to the type II coronins. Coronin 5 was highly expressed Anders Eriksson et al. compared the DNA methylation pro- in brain and directly binds to F-actin in vitro. Immunocyto- files between normal-weight and obese children between 9 to chemical analysis showed that Coronin 5 accumulated at 13 years old; they found that obese children showed signifi- neurite tips and stress fibers in mice. Furthermore, Coronin 5 cantly lower methylation levels at a CpG site near to Coronin was accumulated at focal adhesion via vinculin, which is a 7 [88]. Recent studies revealed that Coronin 7 is highly ex- major component of focal contacts [14]. pressed in brain regions of regulating appetite and energy balance such as hypothalamus, striatum and locus coeruleus 7. CORONIN 6 [13]. In mice and Drosophila, Coronin 7 expression is asso- Coronin 6 (HGNC name: Coronin 6, HGNC symbol: ciated with the regulation of energy homeostasis [80]. These CORO 6) was first identified as a differentially regulated data indicates that Coronin 7 participated in the biosynthetic protein in rat skeletal muscle upon denervation and was pathway and energy homeostasis pathway, but it do need highly concentrated at the NMJ (neuromuscular junction) more experiments to provide a complete functional under- [80, 81] (Table 1). High density of neurotransmitter recep- standing and molecular characterization of Coronin 7 in tors at the postsynaptic apparatus is responsible for the neu- those processes. rotransmission. The NMJ, formed between skeletal muscle membrane and the motor nerve terminal, is required for neu- 9. PERSPECTIVES romuscular transmission and muscle activities [82, 83]. As Although the mammalian coronins have been signifi- neurotransmitter receptors, Acetylcholine receptors cantly involved in different human diseases, we still know (AChRs), which are densely packed on the postsynaptic little about the transcriptional regulation of coronins. The muscle membrane through anchoring on actin cytoskeletal trans-factors that are binding to or interacting with the pro- network at the NMJ, is deed for the efficient synaptic trans- moter of coronin need to be careful delineated. Furthermore, mission [84]. The mutations found in the AChRs are the ma- the signaling pathways that mammalian coronins were in- jority mutations causing congenital myasthenic syndrome volved are still largely unknown. Understanding of these (CMS), which is an inherited neuromuscular disorder caused issues may give better insight of the roles of coronins in hu- by defects of NMJ[83]. Coronin 6 is highly enriched at NMJ man diseases, and might provide potential therapeutic targets of adult [79]. Utilizing the C-terminal region and a con- for the coronins involved diseases. served Arg29 residue at the N-terminus, Coronin 6 forms complex with AChRs and actin. Knockdown of the Coronin ABBREVIATIONS 6 in the mouse skeletal muscle fibers destabilized AChR complexes as well as reduced the complexity of AChR clus- 2B8a = ACH-2B8a The Coronin Family and Human Disease Current Protein and Peptide Science, 2016, Vol. 17, No. ?? 7

AChRs = Acetylcholine receptors Foundation of Fujian Province (Grant No. 2015D001), the Scientific Foundation of Fuzhou Health Department (Grand Arp2/3 = Actin-Related Proteins ARP2 and ARP3 N0. 2013-S-wq18), the Mengchao Hepatobiliary Hospital of BMDMs = Primary Bone Marrow-Derived Macro- Fujian Medical University (Grand No. QDZJ-2014-004), the phages Science and Technology Bureau of Fuzhou City (Grand No. cAMP = Cyclic Adenosine Monophosphate 2014-S-139-1), the Fujian Provincial Health and Family Planning Commission (Grand No. 2014-2-41) and Research C.elegans = Caenorhabditis elegans Development special Fund of indirectly affiliated hospital of CMS = Congenital myasthenic syndrome Fujian Medical University (Grand No.FZS13004Y). CTSK = Cathepsin K REFERENCES DNA = Deoxyribonucleic Acid [1] De Hostos, E.L.; Bradtke, B.; Lottspeich, F.; Guggenheim, R.; EST = Expressed Sequence Tag Gerisch, G. 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Received: September 17, 2015 Revised: October 31, 2015 Accepted: November 07, 2015