Vps-C complexes: gatekeepers of endolysosomal traffic

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Genetic studies in yeast, plants, insects, and mammals have identified four universally conserved proteins, together called Vps Class C, that are essential for late endosome and lysosome assembly and for numerous endolysosomal trafficking pathways, including the terminal stages of autophagy. Two Vps-C complexes, HOPS and CORVET, incorporate diverse biochemical functions: they tether membranes, stimulate Rab nucleotide exchange, guide SNARE assembly to drive membrane fusion, and possibly act as ubiquitin ligases. Recent studies offer new insight into the complex relationships between Vps-C complexes and their cognate Rab small GTP-binding (G-)proteins at endosomes and lysosomes. Accumulating evidence supports the view that Vps-C complexes implement a regulatory logic that governs endomembrane identity and dynamics.

Introduction

The Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and protein sorting) are found on endosomes and lysosomes, where they control membrane traffic by keeping a close eye on the membrane fusion machinery. HOPS and CORVET are essential for the maturation, integrity, and inheritance of late endosomes and vacuolar lysosomes, and appear to control all traffic passing into and through these organelles (Figure 1). Hence, Vps-C complexes are likely central regulators of a multitude of cellular and physiological processes associated with late endocytic organelles, including downregulation of growth factor receptors and nutrient transporters [1, 2], disposal and recycling of cytoplasmic components through autophagy [3, 4, 5], cholesterol and lipid metabolism [6, 7], and antigen processing and presentation [8, 9]. In this review we focus on the yeast Vps-C complexes because they have been subjected to the closest scrutiny. However, conserved complexes appear to carry out similar functions in all eukaryotes [10, 11, 12, 13].

Section snippets

Vps-C complexes: molecular organization

Classical genetic screens in Saccharomyces cerevisiae identified 41 VPS (vacuole protein sorting) genes [14], and over a dozen PEP (peptidase sorting) genes [15], involved in delivery of cargo to the yeast vacuole. Mutations in four of these caused the severe Class C phenotype, with mutant cells lacking an identifiable vacuolar lysosome. The proteins encoded by these genes, Vps11 (Pep5), Vps16, Vps18 (Pep3), and Vps33, associate to form the stable Vps-C core complex [16, 17]. The VPS family

Endosome maturation and Rab/Vps-C complex conversion

Nearly 20 years ago it was recognized that mammalian early endosomes are decorated with Rab5, while late endosomes and lysosomes bear Rab7 [43]. The discovery that CORVET and HOPS complexes specifically interact with endosomal and lysosomal Rabs, and the identification of intermediate complexes containing both CORVET and HOPS accessory subunits [10, 28••, 31], suggests a range of plausible models for compartmental maturation during endolysosomal transport. Through exchange of Vps3 for Vps39,

Future directions

Vps-C complexes control the locations, timing, specificity, and integrity of fusion in the terminal branches of the endocytic system. Besides the fundamental concern of maintaining organelle identity, inappropriate delivery of cargo to the lysosome can result in improper proteolytic activation, as illustrated by mistaken lysosomal maturation of trypsinogen to trypsin, which leads to intracellular proteolysis and pancreatitis [62]. Fusion is an inherently dangerous business, as demonstrated by

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Dr. C. Hickey and members of the Merz lab for critical reading of the manuscript. This work was supported by grant GM077349 from the National Institutes of Health.

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