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Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function

Key Points

  • 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.

  • Most lysosomal hydrolases acquire a mannose-6-phosphate (M6P) tag in the Golgi complex. This tag is recognized in the trans-Golgi network (TGN) by M6P receptors (M6PRs) that target the lysosomal hydrolases to the endo-lysosomal pathway. M6PR-independent pathways for the transport of lysosomal hydrolases do exist but, like the pathways for the transport of lysosomal membrane proteins (LMPs), they are mostly undetermined.

  • Recently, the LMP lysosome integral membrane protein 2 was found to be required for the M6PR-independent transport of the lysosomal hydrolase β-glucocerebrosidase to the lysosome. This finding indicates a novel role for LMPs in intracellular protein transport and links the lysosomal targeting of an LMP to a lysosomal hydrolase, albeit by an as yet unidentified pathway.

  • Recent studies provide evidence for both clathrin- and non-clathrin-mediated exits for LMPs from the TGN, which would allow for a timely and targeted delivery of LMPs to distinct endosomal intermediates. This is further supported by the presence of multiple sorting signals in the cytosolic tails of some LMPs, the observation that domains other than the cytosolic tails can be involved in lysosomal targeting and the occurrence of post-translational modifications that can provide fine-tuning of the sorting signals.

  • The significance of understanding LMP trafficking is further illustrated by the ongoing discovery of new and unexpected roles for LMPs in cellular physiology and of mutations in LMPs that lead to lysosomal dysfunction and disease. An important emerging theme is that the absence or presence of LMPs can essentially change the properties of the target compartment; for example, its acidity, fusogenicity, catabolic capacity, dynamics and drug resistance and the availability of cytoplasmic substrates.

  • Elucidating alternative pathways for the delivery of lysosomal proteins is a major challenge for future studies and is of key importance to expand our knowledge of lysosome biogenesis and to understand the pathologies that are associated with lysosomal dysfunctioning.

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.

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Figure 1: Major functions of lysosomal membrane proteins.
Figure 2: Possible interactions between the biosynthetic and endocytic pathways.
Figure 3: Intra-endosomal distribution of lysosomal membrane proteins.
Figure 4: M6PR-dependent and -independent targeting of lysosomal hydrolases to the lysosome.

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Acknowledgements

We want to thank our colleagues for their input and many discussions. We express our special thanks to M. van Peski, J. Schröder, M. Schwake, R. Scriwanek and V. Oorschot for help with preparation of the original figures, and H. Geuze, M. Pols and R. Galmes for their comments on the manuscript. J.K. is the recipient of VICI grant 918.56.611 of the Netherlands Organization for Scientific research (NWO). P.S. is the recipient of DFG grants GRK1459 and SA683/5-1 and of the Center of Excellence 'Inflammation at Interfaces' grant. Cells used in figure 3, part c, were courtesy of M. Schwake, Department of Biochemistry, Christian-Albrechts University, Kiel, Germany.

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DATABASES

OMIM

AMRF

Danon disease

Hermansky–Pudlak syndrome 2

I-cell disease

mucolipidosis type IV

sialidosis

XMEA

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Glossary

Lysosome-related organelle

(LRO). A cell-type-specific organelle belonging to a family that includes melanosomes, platelet-dense bodies and cytotoxic T cell granules. LROs contain subsets of lysosomal proteins in addition to cell-type-specific proteins.

Tetraspanin

A member of a conserved protein family with four transmembrane domains and two extracellular loops. Tetraspanins act as scaffolding proteins, anchoring multiple proteins to a specific area at the plasma membrane.

Trans-Golgi network

(TGN). A convoluted membrane compartment at the trans side of the Golgi complex that mediates sorting and transport of proteins to various cellular destinations.

Rab protein

A member of a family of small GTPases that, when associated with the cytosolic leaflet of the endosomal limiting membrane, can initiate the formation of functional microdomains.

HRS

(Hepatocyte growth factor-regulated tyrosine kinase substrate; also known as ESCRT0). A cytosolic protein that is involved in the recognition of ubiquitylated cargo at endosomes, which initiates the recruitment of the ESCRT complex.

Clathrin

A protein that forms a coat which has a major role in the formation of transport vesicles. The coat consists of multiple triskelions, which are composed of three clathrin heavy chains and three light chains.

Retromer

A heterotetrameric protein complex that associates with the cytosolic leaflet of the endosomal limiting membrane. The mammalian retromer consists of a sorting nexin dimer composed of a still-undefined combination of SNX1, SNX2, SNX5 or SNX6 and the cargo recognition trimer VPS26–VPS29–VPS35.

AP1

A member of the heterotetrameric family of adaptor proteins involved in membrane trafficking, which also includes AP2, AP3 and AP4.

ESCRT

(Endosomalsorting complexes required for transport). Endosomal sorting machinery consisting of four complexes ESCRT0, ESCRTI, ESCRTII and ESCRTIII plus several accessory components. ESCRT components recognize ubiquitylated cargoes, deform the endosomal membrane and catalyse the formation of ILVs containing the sorted cargo.

Exosome

A small vesicle that initially exists as an ILV in the lumen of LEs or MVBs. They are called exosomes once released, following fusion of LEs and MVBs with the plasma membrane. Exosomes are thought to have key roles in antigen presentation, cell-to-cell communication, the pathogenesis of retroviral infections and prion disease.

Dendritic cell

A potent antigen-presenting cell that is part of the mammalian immune system. Its main function is to process antigen material and present it, in the context of the MHC class II complex, on its surface to other cells of the immune system.

SNARE

(Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor). A member of a family of membrane-tethered coiled-coil proteins that regulate fusion reactions and target specificity in the vacuolar system. They can be divided into vesicle (v)-SNAREs and target (t)-SNAREs on the basis of their membrane localization.

GGA protein

(Golgi-localized, γ-ear-containing, Arf-binding protein). A member of a family of monomeric adaptor proteins. In mammals there are three different GGA proteins: GGA1, GGA2 and GGA3.

Autophagosome

A double-membrane vesicle that forms at an early stage of the autophagic pathway and can fuse with endosomes and lysosomes for degradation of its contents.

Lysosomal cell death

Apoptosis induced by permeabilization of the lysosomal membrane and the subsequent release of cathepsins into the cytosol. The mechanism of membrane permeabilization is not yet known.

Immunological synapse

The interface between an antigen-presenting cell and a lymphocyte, consisting of a cluster of T cell receptors and a ring of adhesion molecules.

Bacterial type III secretion system

A specialized, needle-like, multiprotein structure in Gram-negative bacteria that is involved in the direct secretion of proteins from the bacterial cell to the host.

Phagosome

A vacuole formed around a particle for example, a pathogenic microorganism absorbed by phagocytosis that can mature into a degradative compartment by fusion with lysosomes.

Autolysosome

A single-membrane vesicle that forms at a late stage of the autophagic pathway by fusion of autophagosomes with endosomes or lysosomes and that contains degradative enzymes obtained after fusion.

Periodontis

A common inflammatory disease of the supporting tissues of the teeth that leads to resorption of alveolar bone and eventually to tooth loss.

Chaperone-mediated autophagy

A direct pathway for transporting cytosolic proteins over the lysosomal limiting membrane and into the lysosome lumen for degradation.

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Saftig, P., Klumperman, J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10, 623–635 (2009). https://doi.org/10.1038/nrm2745

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