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Lysosome Biogenesis and Lysosomal Membrane Proteins: Trafficking Meets Function

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Lysosome Biogenesis and Lysosomal Membrane Proteins: Trafficking Meets Function FOCUS ON ENDOCYTOREVIEWSSIS Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function Paul Saftig* and Judith Klumperman‡ Abstract | Lysosomes are the primary catabolic compartments of eukaryotic cells. They degrade extracellular material that has been internalized by endocytosis and intracellular components that have been sequestered by autophagy. In addition, specialized cells contain lysosome-related organelles that store and secrete proteins for cell-type-specific functions. The functioning of a healthy cell is dependent on the proper targeting of newly synthesized lysosomal proteins. Accumulating evidence suggests that there are multiple lysosomal delivery pathways that together allow the regulated and sequential deposition of lysosomal components. The importance of lysosomal trafficking pathways is emphasized by recent findings that reveal new roles for lysosomal membrane proteins in cellular physiology and in an increasing number of diseases that are characterized by defects in lysosome biogenesis. Lysosome-related organelle Lysosomes are ubiquitous organelles that constitute the limiting membrane and have diverse functions, including (LRO). A cell-type-specific primary degradative compartments of the cell. They acidification of the lysosomal lumen, protein import from organelle belonging to a family receive their substrates through endocytosis, phago­ the cytosol, membrane fusion and transport of degrada­ that includes melanosomes, cytosis or autophagy (FIGS 1,2). The catabolic function of tion products to the cytoplasm8 (FIG. 1). The most abun­ platelet-dense bodies and lysosomes is complemented by lysosome-related organelles dant LMPs are lysosome­associated membrane protein 1 cytotoxic T cell granules. LROs contain subsets of lysosomal (LROs), such as melanosomes, lytic granules, major histo­ (LAMP1), LAMP2, lysosome integral membrane pro­ proteins in addition to compatibility complex (MHC) class II compartments and tein 2 (LIMP2; also known as SCARB2) and the tetraspanin cell-type-specific proteins. platelet­dense granules1. LROs share many properties CD63 (see Supplementary information S1 (table)). with lysosomes, but they also contain cell­type­specific Lysosome biogenesis requires integration of the Tetraspanin (FIG. 2) A member of a conserved proteins and might require additional cellular machinery endocytic and biosynthetic pathways of the cell . 2,3 protein family with four for their biogenesis . Lysosomes and LROs are involved Lysosomal targeting of newly synthesized lysosomal pro­ transmembrane domains and in various physiological processes, such as cholesterol teins can be direct, from the trans-Golgi network (TGN) to two extracellular loops. homeostasis, plasma membrane repair, bone and tissue the endosomal system, or indirect, involving transport Tetraspanins act as scaffolding remodelling, pathogen defence, cell death and cell signal­ to the plasma membrane and subsequent endocytosis. The proteins, anchoring multiple (FIG. 1) proteins to a specific area at ling . These complex functions make the lysosome best understood direct pathway is the mannose­6­phosphate the plasma membrane. a central and dynamic organelle and not simply the dead receptor (M6PR)­mediated transport of lysosomal hydro­ end of the endocytic pathway. lases9,10. By contrast, remarkably little is known about the *Department of Two classes of proteins are essential for the function of structural and molecular machinery for the transport Biochemistry, Christian- lysosomes: soluble lysosomal hydrolases (also referred to of LMPs to lysosomes. The significance of tightly regu­ Albrechts University, as acid hydrolases) and integral lysosomal membrane pro­ lated LMP trafficking is illustrated by recent findings that Kiel, D-20498 Germany. teins (LMPs). Each of the 50 known lysosomal hydrolases describe new and unexpected roles for LMPs in cellular ‡Department of Cell Biology, University Medical Centre targets specific substrates for degradation, and their col­ physiology. It is becoming apparent that LMPs can impose Utrecht, 3584CX Utrecht, lective action is responsible for the total catabolic capac­ specific functions onto the organelles through which The Netherlands. ity of the lysosome. In addition to bulk degradation and they are transported or in which they reside, such as the e-mails: J.Klumperman@ pro­protein processing, lysosomal hydrolases are involved endoplasmic reticulum (ER), lysosomes and the plasma umcutrecht.nl; in antigen processing, degradation of the extracellular membrane. Their importance is further highlighted by [email protected] 4 doi:10.1038/nrm2745 matrix and initiation of apoptosis . The mammalian the discovery of an increasing number of gene mutations 5 11 Published online lysosome contains ~25 LMPs , but additional LMPs are that lead to lysosomal dysfunction and disease (TABLE 1). 12 August 2009 being revealed5–7. LMPs reside mainly in the lysosomal In addition, various knockout mice and non­mammalian NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 10 | SEPTEMBER 2009 | 623 © 2009 Macmillan Publishers Limited. All rights reserved REVIEWS Macroautophagy Isolation Autophagosome membrane Chaperone-mediated Autolysosome autophagy Macroparticle + Degraded Phagocytosis H protein ADP+Pi V-type Cytosolic protein ATP H+-ATPase H+ Lysosomal exocytosis and Phagosome plasma membrane repair LAMP CLC7 + + H Cl– H+ H + H+ Lysosome H+ H + + + H + H H H+ H LIMP2 SYT7 Phagolysosome CD63 NPC1 Cathepsin MHC class II Lysosomal cell death compartment H+ MHC class II Cholesterol Exosome release Amino acids Cholesterol homeostasis Plasma and hexoses membrane MHC class II-dependent antigen presentation Antigenic peptide Peptide Figure 1 | Major functions of lysosomal membrane proteins. The lysosome is a central, acidic organelle that is involved in the degradation of macromolecules through the activity of lysosomal hydrolases. LysosomesNature Re viearews crucial | Mol ecularfor the Ce ll Biology maturation of phagosomes to phagolysosomes in phagocytosis, which is important for cellular pathogen defence. The macroautophagy pathway mediates the turnover of cytoplasmic components, such as organelles and large complexes, and is involved in cell death and proliferation. Macroautophagy depends on the fusion of lysosomes with autophagosomes to create autolysosomes, in which degradation occurs. Macroautophagy and chaperone-mediated autophagy, a direct lysosomal transport process for cytosolic proteins, are regulated by lysosome-associated membrane proteins (LAMPs). Lysosomal exocytosis and plasma membrane repair are Ca2+ and synaptotagmin 7 (SYT7)-dependent fusion events, which are possibly involved in pathogen entry, autoimmunity and neurite outgrowth. The lysosomal cell death pathway is triggered by a release of lysosomal cathepsins through an unknown mechanism. Cellular cholesterol homeostasis is controlled by lysosomal cholesterol efflux through Niemann–Pick C1 protein (NPC1). Major histocompatibility complex (MHC) class II-dependent antigen presentation requires lysosomal proteases and membrane proteins. The release of exosomes is thought to be involved in adaptive immune responses. Lysosomal membrane proteins are also involved in the transport of newly synthesized hydrolases to the lysosome (for example, lysosomal integral membrane protein 2 (LIMP2)) and across the lysosomal membrane (for example, the V-type H+-ATPase complex and chloride channel protein 7 (CLC7)) . model organisms have highlighted the role of LMPs in cell through vesicular transport carriers, tubular connections Trans-Golgi network 18–20 (TGN). A convoluted membrane physiology (see Supplementary information S1 (table)). and kiss­and­run fusion events . compartment at the trans side Here, we give an overview of the cellular pathways The widely used distinction between early endosomes of the Golgi complex that involved in lysosome biogenesis, with a focus on the bio­ (EEs) and late endosomes (LEs)12 is based on functional mediates sorting and transport synthetic pathways that are independent of M6PR func­ and biological characteristics, but oversimplifies the com­ of proteins to various cellular destinations. tioning. In addition, we discuss the putative and emerging plexity of the endocytic pathway. This was exempli fied roles of LMPs in the transport of proteins and organelles by a recent immunoelectron microscopy (IEM) study Rab protein and the consequences of their impaired trafficking for linking the molecular make­up of endosomes with their A member of a family of small human health. ultrastructural characteristics21. Distinct EE marker GTPases that, when associated proteins showed different distributions, ranging from a with the cytosolic leaflet of the endosomal limiting membrane, Endocytic pathways to the lysosome restricted localization on early­stage EEs (for example, can initiate the formation of The degradative endocytic pathway starts at the plasma early endosome antigen 1 (EEA1)) to a more widespread functional microdomains. membrane and ends in lysosomes. Between these two distribution on other EEs and on early­stage LEs (for ‘stations’, endocytosed cargo passes through a range of example, the Rab proteins RAB11 and RAB4, and HRS (also HRS (FIG. 2) (Hepatocyte growth endosomal intermediates that are distinguished known as ESCRT0)). These observations indicate that factor-regulated tyrosine by their content, molecular make­up, morphology and functionally different intermediates of EEs and LEs can kinase substrate; also
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