Atypical parkinsonism–associated retromer mutant alters endosomal sorting of specific cargo proteins

McMillan, Kirsty J; Gallon, Matthew; Jellett, Adam P.; Clairfeuille, Thomas; Tilley, Frances C.; McGough, Ian J.; Danson, Chris M.; Heesom, Kate J; Wilkinson, Kevin A.; Collins, Brett M.; Cullen, Peter J.

doi:10.1083/jcb.201604057

Cited by 40 publications

(48 citation statements)

References 44 publications

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“…We have previously used GFP-nanotrap immuno-capture coupled with SILAC (stable isotope labelling with amino acids in culture)-based quantitative proteomics to provide molecular insight into the assembly of endosomal sorting complexes 18, 27, 38 . To establish this methodology for SNX17, we first validated that GFP-tagging of SNX17 did not adversely affect its function.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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Following endocytosis and entry into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are alternatively retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multi-protein 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 the CCC 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 new endosomal retrieval and recycling pathway.

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Section: Resultsmentioning

confidence: 99%

“…Given that mechanistic analysis of endosomal cargo retrieval and recycling is allowing a greater understanding of the patho-etiology of human diseases 27–31 , we have sought to identify and characterise evolutionary conserved retromer-independent cargo sorting machinery(s).…”

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confidence: 99%

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

et al. 2017

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“…Insofar, all genetic mutations identified in SNX27 or retromer in humans have been linked to severe neuropathologies including Alzheimer’s disease [83], Parkinson’s disease [84, 85], Down syndrome [86] and infantile epilepsy [87] for recent reviews see [88, 89]. Accordingly, lowered expression of SNX27 or retromer reduces the surface cell levels of several cargo known to influence synaptic neurotransmission (N-methyl-D-aspartate receptors; NMDARs [90] and AMPARs[91], neuronal signaling and excitably (β 2 AR [90], GIRK2a [92] mGLuR5 [93]), glial cell differentiation (GPCR 17; GPR17 [94]) and, more recently, limiting the distribution of amyloid precursor protein (APP), a precursor linked to the onset and progression of Alzheimer’s disease [95].…”

Section: Figurementioning

confidence: 99%

GPCR Signaling and Trafficking: The Long and Short of It

Pavlos

Friedman

2017

Trends in Endocrinology & Metabolism

170

121

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Emerging findings disclose unexpected components of G protein-coupled receptor (GPCR) signaling and cell biology. Select GPCRs exhibit classical signaling that is restricted to cell membranes and newly described persistent signaling that depends on internalization of the GPCR bound to β-arrestins. Termination of non-canonical endosomal signaling requires intraluminal acidification and sophisticated protein trafficking machineries. Recent studies reveal the structural determinants of the trafficking chaperones. This review summarizes advances in GPCR signaling and trafficking with a focus on the parathyroid hormone receptor as prototype, and the actin-SNX27-retromer tubule complex, an endosomal sorting hub responsible for recycling and preservation of cell surface receptors. The findings are integrated into a model of PTHR trafficking with implications for signal transduction, bone growth, and mineral-ion metabolism.

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“…The rat SNX27 PDZ domain and human VPS26A proteins were purified as described previously (19,43,72). Proteins were gel filtered into ITC buffer (50 mM Tris, pH 8, and 100 mM NaCl) using a Superose 200 column.…”

Section: Itcmentioning

confidence: 99%

Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

McMillan

Banks

Hellel

et al. 2020

Preprint

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The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27associated pathologies we have performed unbiased proteomics to identify new neuronal SNX27-dependent cargoes, and identified proteins linked to excitotoxicity (SLC1A3, SLC4A7, SLC6A11), epilepsy, intellectual disabilities and working memory deficits (KCNT2, ADAM22, KIDINS220, LRFN2).Focusing on the synaptic adhesion molecule leucine-rich repeat and fibronectin type-III domain-containing protein 2 (LRFN2), we establish that SNX27 binds to LRFN2 and is responsible for regulating its endosomal sorting. LRFN2 associates with AMPA receptors and knockdown of LRFN2 phenocopies SNX27 depletion in decreasing surface expression of AMPA receptors, reducing synaptic activity and attenuating hippocampal long-term potentiation.Our evidence suggests that, in contrast to previous reports, SNX27 does not directly bind to AMPA receptors, and instead controls AMPA receptor-mediated synaptic transmission and plasticity indirectly through the endosomal sorting of LRFN2. Overall, our study provides new molecular insight into the perturbed function of SNX27 and LRFN2 in a range of neurological conditions.

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Atypical parkinsonism–associated retromer mutant alters endosomal sorting of specific cargo proteins

Cited by 40 publications

References 44 publications

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

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

GPCR Signaling and Trafficking: The Long and Short of It

Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

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