Dataset Information

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

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 which orchestrates cargo retrieval and recycling and importantly, is biochemically and functionally distinct to the established retromer pathway. Composed of a heterotrimer of DSCR3, C16orf62 and VPS29, and bearing striking similarity with retromer, we have called this complex ‘retriever’. 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, which require SNX17-retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Disease Free

SUBMITTER: Kerrie McNally

LAB HEAD: Peter J Cullen

PROVIDER: PXD007230 | Pride | 2018-01-15

REPOSITORIES: Pride

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

McNally Kerrie E KE Faulkner Rebecca R Steinberg Florian F Gallon Matthew M Ghai Rajesh R Pim David D Langton Paul P Pearson Neil N Danson Chris M CM Nägele Heike H Morris Lindsey L LL Singla Amika A Overlee Brittany L BL Heesom Kate J KJ Sessions Richard R Banks Lawrence L Collins Brett M BM Berger Imre I Billadeau Daniel D DD Burstein Ezra E Cullen Peter J PJ

Nature cell biology 20170911 10

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 VPS ...[more]

PMID: 28892079

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Project description:T lymphocyte recognition of antigenic peptides on the surface of antigen-presenting cells (APC) leads to immune synapse formation (IS). By analogy with the nervous synapse, this cell-cell communication model requires the formation of highly organized structures that delimit an active zone of membrane traffic. For T cells to connect antigen recognition with the biological response, receptors and signaling proteins must be recycled. Sorting nexin 27 (SNX27) is an endosomal protein best known for its role in recycling PDZ (PSD95, Dlg1, ZO-1)-interacting neuronal proteins via the retromer transport machinery. Alteration of this sorting pathway leads to neurodegeneration and is associated to Down syndrome, Alzheimer’s and Parkinson’s diseases. In T lymphocytes, SNX27 interacts with diacylglycerol kinase zeta (DGKz), which provides a mechanistic link between diacylglycerol metabolism and membrane trafficking. Following antigen recognition, SNX27-positive endosomes polarize to the IS and a PDZ-dependent SNX27 pool accumulates at the cell-cell contact area. To test for additional SNX27 functions, we carried out proteomic analysis of the SNX27 interactome purified from T cells in contact with APC, and identified SNX27 interaction with the retromer and with members of the WASH (Wiskott-Aldrich syndrome protein and SCAR homologue) complex. This finding indicates the conserved nature of the SNX27/WASH/retromer complex in hematopoietic cells and suggests similarity between neurological diseases and abnormal immune/inflammatory responses. We also found PDZ-dependent SNX27 cargoes, including modulators of cytoskeletal reorganization such as zona occludens-2 (ZO-2). ZO-2, a cytosolic component of epithelial cell-cell junctions, localized to the IS, and SNX27 silencing affected ZO-2 stability at the synapse. This study broadens our knowledge of SNX27 function in T lymphocytes, and suggests that pathways that delimit polarized structures in epithelial systems also participate in IS regulation.

			Action	DRS
	100516_Set3.msf	Msf
	APooled1-6.msf	Msf
	BPooled1-6.msf	Msf
	CPooled1-6.msf	Msf
	Set3_Slice_1.raw	Raw