Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling

Nat Cell Biol. 2017 Oct;19(10):1214-1225. doi: 10.1038/ncb3610. Epub 2017 Sep 11.

Abstract

Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α5β1 integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17-retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Membrane / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Endosomes / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kinetics
  • Models, Molecular
  • Multiprotein Complexes
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Stability
  • Protein Transport
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / metabolism*
  • Proteolysis
  • Proteomics / methods
  • RNA Interference
  • Sorting Nexins / genetics
  • Sorting Nexins / metabolism
  • Structure-Activity Relationship
  • Transfection
  • Vesicular Transport Proteins / chemistry
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • CCDC22 protein, human
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Neoplasm Proteins
  • Proteins
  • SNX17 protein, human
  • Sorting Nexins
  • VPS26C protein, human
  • VPS29 protein, human
  • VPS35L protein, human
  • Vesicular Transport Proteins