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To degrade or not to degrade: mechanisms and significance of endocytic recycling

Abstract

Newly endocytosed integral cell surface proteins are typically either directed for degradation or subjected to recycling back to the plasma membrane. The sorting of integral cell surface proteins, including signalling receptors, nutrient transporters, ion channels, adhesion molecules and polarity markers, within the endolysosomal network for recycling is increasingly recognized as an essential feature in regulating the complexities of physiology at the cell, tissue and organism levels. Historically, endocytic recycling has been regarded as a relatively passive process, where the majority of internalized integral proteins are recycled via a nonspecific sequence-independent ‘bulk membrane flow’ pathway. Recent work has increasingly challenged this view. The discovery of sequence-specific sorting motifs and the identification of cargo adaptors and associated coat complexes have begun to uncover the highly orchestrated nature of endosomal cargo recycling, thereby providing new insight into the function and (patho)physiology of this process.

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Acknowledgements

The authors are extremely grateful to their laboratory colleagues and to M. Babst, S. Caplan, J. Carlton, B. Collins, J. Gruenberg, M. Puthenveedu, A. Roux, M. v. Zastrow and M. Zerial for many thoughtful discussions. P.J.C. is supported by the Wellcome Trust (104568/Z/14/Z), the Medical Research Council (MR/P018807/1) and the Lister Institute. F.S. is supported by an Emmy Noether Fellowship of the Deutsche Forschungsgemeionschaft (DFG).

Reviewer information

Nature Reviews Molecular Cell Biology thanks V. Hsu and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Both authors researched data for the article, contributed to discussion of the content, wrote the article and edited the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Peter J. Cullen or Florian Steinberg.

Supplementary information

Supplementary Table 1

Glossary

Intraluminal vesicles

(ILVs). Small, cargo-enriched vesicles within the lumen of a maturing late endosome.

Endosomal sorting complexes required for transport

(ESCRT). Protein complexes that mediate the sorting of ubiquitylated cargo into intraluminal vesicles for degradation in lysosomes.

Sorting motifs

Usually unstructured linear peptide sequences present in the cytoplasmic tail of cargo proteins that, by engaging coat complexes, control the sorting of said cargo through intracellular membrane trafficking.

Sorting nexin (SNX) family

A large and diverse family of endosome-localized, peripheral membrane proteins defined by the presence of a PX domain.

β-Amyloid precursor protein

(APP). An integral membrane protein highly expressed in neuronal synapses. Proteolytic cleavage of APP generates the toxic β-amyloid polypeptide that contributes to Alzheimer disease.

Amphid sensory organ

The principal olfactory organ of nematodes.

Haemocyte

A cell of the haemolymph in invertebrates.

Amyloids

Protein aggregates that can form fibrils, often associated with neurodegenerative diseases, such as Alzheimer disease.

Macroautophagy

A degradative pathway in which a nutrient-starved cell sequesters cytoplasmic content into double membraned vesicles for lysosomal degradation.

Chaperone-mediated autophagy

A specialized form of autophagy in which chaperone proteins directly shuttle cytosolic proteins into the lysosomal lumen through lysosome-associated membrane glycoprotein 2 (LAMP2A)-mediated channels.

Wiskott–Aldrich syndrome and SCAR homologue (WASH) complex

Pentameric multiprotein complex that generates branched actin networks on the endosomal membrane.

BAR (Bin–Amphiphysin–Rvs) domain

A frequently occurring protein domain with α-helical coiled coils. The domains can dimerize to form a banana-shaped structure. Oligomerization of BAR domains can deform cellular membranes.

Hereditary spastic paraplegia

(HSP). A group of inheritable diseases characterized by progressive gait disorders due to dysfunction of motor neurons in the spinal cord.

Microglia

Macrophage-related immune cells of the central nervous system.

Eps15 homology domain (EHD) family

A family of four proteins (EHD1–EHD4) that possess structural similarities to dynamin and function in intracellular trafficking.

F-BAR domain

(FCH-homology BAR domain). A BAR domain found in proteins that couple membrane remodelling with actin dynamics.

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Further reading

Fig. 1: The endolysosomal network.
Fig. 2: ESCRT-mediated degradative cargo sorting.
Fig. 3: Retrieval mechanisms.
Fig. 4: BAR domain-containing proteins in endosome tubule formation.