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Receptor downregulation and multivesicular-body sorting

Nature Reviews Molecular Cell Biology volume 3, pages 893–905 (2002)Cite this article

Key Points

  • The multivesicular-body (MVB) sorting pathway delivers transmembrane proteins and lipids into small vesicles that invaginate into the lumen of the endosome. MVBs fuse with the vacuole/lysosome and the vesicles and their contents are degraded by the hydrolases that are contained in the lumen of the vacuole/lysosome.

  • A crucial function of the MVB protein sorting pathway is the downregulation of activated cell-surface receptors.

  • Ubiquitin functions as an important signal for the selection of MVB cargoes and also seems to modulate the activity of trans-acting factors in the MVB pathway.

  • A large number of trans-acting factors that are required for MVB sorting have recently been identified, including the class E vacuolar protein sorting (Vps) proteins in yeast, phosphoinositide kinases and ubiquitin ligases.

  • The MVB sorting machinery is required for a growing list of cellular functions that include receptor downregulation, developmental signalling, regulation of the immune response and even the budding of certain viruses like human immunodeficiency virus (HIV).

Abstract

The sorting of proteins into the inner vesicles of multivesicular bodies is required for many key cellular processes, which range from the downregulation of activated signalling receptors to the proper stimulation of the immune response. Recent advances in our understanding of the multivesicular-body sorting pathway have resulted from the identification of ubiquitin as a signal for the efficient sorting of proteins into this transport route, and from the discovery of components of the sorting and regulatory machinery that directs this complex process.

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Figure 1: Receptor downregulation in mammalian and yeast cells.
Figure 2: Regulation of cargo entry into the multivesicular-body sorting pathway.
Figure 3: Ubiquitin-recognition by trans-acting components of the multivesicular-body sorting pathway.
Figure 4: Multivesicular bodies in cellular physiology and disease.

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Acknowledgements

We wish to thank L. Hicke, B. Horazdovsky, C. Joaziero, R. Piper and W. Sundquist for communicating their data before publication. We also thank R. Hampton, I. Mellman, M. Farquhar and R. Piper for many helpful discussions.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, 55905, Minnesota, USA

    David J. Katzmann

  2. Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, 80309-0347, Colorado, USA

    Greg Odorizzi

  3. Department of Cellular and Molecular Medicine, and Howard Hughes Medical Institute, University of California San Diego School of Medicine, La Jolla, 92093–0668, California, USA

    Scott D. Emr

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  1. David J. Katzmann
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  2. Greg Odorizzi
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DATABASES

OMIM

Niemann–Pick type C

Swiss-Prot

Cbl

CPS

CXCR4

EGF

EGFR

Eps15

Hrs

Rsp5

SKD1

Snf7

Ste2

Tsg101

ubiquitin

Vps4

Vps28

FURTHER INFORMATION

Scott Emr's laboratory

Glossary

EMBRYONIC PATTERNING

The differentiation of cell lines that lead to developed tissues.

VULVAL DEVELOPMENT

A readily accessible genetic system in Caenorhabditis elegans that can be used to study the induction and regulation of epidermal-growth-factor-receptor signalling pathways in vivo.

HAPLOID

Yeast cells can exist as either a diploid (2N chromosome) or haploid (1N chromosome). Deletion or mutation of genes in haploid yeast cells allows the rapid analysis of phenotype.

ATPase

An enzyme that hydrolyses ATP.

26S PROTEASOME

The large protein complex that is responsible for degrading polyubiquitylated proteins.

ɛ-AMINO-ACID GROUP

The amino group on a lysine residue to which ubiquitin is conjugated by an isopeptide bond.

POLYTOPIC

A multi-pass membrane protein.

RETROTRANSLOCATED

The reverse translocation of proteins from the endoplasmic reticulum (ER) lumen that have been recognized as substrates for degradation by the ER-associated degradation (ERAD) pathway.

RING DOMAIN

A cysteine-rich 'RING'-finger domain of 40–60 amino acids (also known as the C3HC4 zinc-finger) that binds two atoms of Zn2+ and might mediate protein–protein interactions. Many RING-domain-containing proteins have been shown to act as E3 ubiquitin ligases.

NUDE MICE

In the context of this review, these are immunodeficient mice that are used to assay tumorigenicity.

AAA-TYPE ATPase

An ATPase family that seems to be predominantly involved in the disassembly of protein complexes.

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Katzmann, D., Odorizzi, G. & Emr, S. Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol 3, 893–905 (2002). https://doi.org/10.1038/nrm973

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