Sorting nexin 27 couples PTHR trafficking to retromer for signal regulation in osteoblasts during bone growth

Chan, Audrey S.; Clairfeuille, Thomas; Landao-Bassonga, Euphemie; Kinna, Genevieve; Ng, Pei Ying; Loo, Li Shen; Cheng, Tak Sum; Zheng, Minghao; Hong, Wanjin; Teasdale, Rohan D.; Collins, Brett M.; Pavlos, Nathan J.

doi:10.1091/mbc.e15-12-0851

Cited by 49 publications

(64 citation statements)

References 85 publications

(114 reference statements)

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“…Finally, because the experiments were of necessity performed with PTHR overexpression, we cannot conclude with certainty whether ASRT or ASRT-independent recycling predominates under physiological conditions. While the present study was under review, a complementary investigation reported compatible findings that additionally demonstrate an important role of SNX27 on PTH actions on skeletal development (88). Global SNX27 knock-out decreased multiple parameters of bone architecture in post-natal mice.…”

Section: Discussionsupporting

confidence: 76%

Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling

McGarvey¹,

Xiao²,

Bowman³

et al. 2016

Journal of Biological Chemistry

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The G protein-coupled parathyroid hormone receptor (PTHR) regulates mineral-ion homeostasis and bone remodeling. Upon parathyroid hormone (PTH) stimulation, the PTHR internalizes into early endosomes and subsequently traffics to the retromer complex, a sorting platform on early endosomes that promotes recycling of surface receptors. The C terminus of the PTHR contains a type I PDZ ligand that binds PDZ domaincontaining proteins. Mass spectrometry identified sorting nexin 27 (SNX27) in isolated endosomes as a PTHR binding partner. PTH treatment enriched endosomal PTHR. SNX27 contains a PDZ domain and serves as a cargo selector for the retromer complex. VPS26, VPS29, and VPS35 retromer subunits were isolated with PTHR in endosomes from cells stimulated with PTH. Molecular dynamics and protein binding studies establish that PTHR and SNX27 interactions depend on the PDZ recognition motif in PTHR and the PDZ domain of SNX27. Depletion of either SNX27 or VPS35 or actin depolymerization decreased the rate of PTHR recycling following agonist stimulation. Mutating the PDZ ligand of PTHR abolished the interaction with SNX27 but did not affect the overall rate of recycling, suggesting that PTHR may directly engage the retromer complex. Coimmunoprecipitation and overlay experiments show that both intact and mutated PTHR bind retromer through the VPS26 protomer and sequentially assemble a ternary complex with PTHR and SNX27. SNX27-independent recycling may involve N-ethylmaleimide-sensitive factor, which binds both PDZ intact and mutant PTHRs. We conclude that PTHR recycles rapidly through at least two pathways, one involving the ASRT complex of actin, SNX27, and retromer and another possibly involving N-ethylmaleimide-sensitive factor.

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Section: Discussionsupporting

confidence: 76%

Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling

McGarvey¹,

Xiao²,

Bowman³

et al. 2016

Journal of Biological Chemistry

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“…This PDZ ligand assumes a Type I consensus sequence (E-T-V-M) that is compatible with the canonical recognition signature of the SNX27-PDZ domain. Parallel studies recently confirmed this engagement, thereby providing a direct molecular link to the ASRT complex [50, 63]. First, a PDZ-dependent interaction was demonstrated between PTHR and SNX27 by combining coimmunoprecipitation studies in HEK293 cells with isothermal titration calorimetry (ITC), the later titrating a series of native and mutant PTHR-PDZ-ligand peptides against the SNX27-PDZ domain.…”

Section: Asrt-mediated Endosome-to-plasma Membrane Recyclingmentioning

confidence: 95%

“…Ablation of β 2 AR suppressed expression of PTH-target genes involved in bone turnover. Further evidence that sustained PTHR signaling is required for normal skeletal development comes from studies showing the interfering with receptors internalized to endosomes in osteoblasts reduces bone mineralization and causes major skeletal deficits [50], as discussed below.…”

Section: What’s In It For Me?mentioning

confidence: 99%

“…More recently, the crystal structure of an extended PTHR PDZ-ligand (EEWETVM) in complex with the SNX27-PDZ domain has also been resolved at near atomic resolution (0.95Å) [50]. Several salient structural features including two acidic residues (Glu −5 and Glu −3 ) that lie upstream of the canonical C-terminal PTHR PDZ binding triplet (TVM) were uncovered and shown to form strong contacts with Arg 58 within the PDZ-domain.…”

Section: The Asrt Complexmentioning

confidence: 99%

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GPCR Signaling and Trafficking: The Long and Short of It

Pavlos

Friedman

2017

Trends in Endocrinology & Metabolism

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161

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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“…SNX27 is directly bound to the retromer subunit VPS26 and simultaneously binds to a multitude of PDZ-and tyrosine-based sorting motifs in the cytosolic tail of its cargo proteins, thereby driving their recycling back to the cell surface (Steinberg et al, 2013;Gallon et al, 2014;Ghai et al, 2013). Retromer and SNX27 have been shown to recycle a wide range of surface molecules, ranging from signalling receptors like the β2-adrenergic receptor (Lauffer et al, 2010) or the parathyroid hormone receptor (PTHR) (Chan et al, 2016;McGarvey et al, 2016), and nutrient transporters (Steinberg et al, 2013) to neuronal glutamate receptors (Wang et al, 2013;Loo et al, 2014;Hussain et al, 2014). Although loss of retromer as well as of the WASH complex is lethal early in embryogenesis (Wen et al, 2011;Gomez et al, 2012), loss of SNX27 is lethal shortly upon birth of genetically modified mice (Cai et al, 2011), highlighting the physiological relevance of SNX27-, retromer-and/or WASH-driven recycling processes.…”

Section: Introductionmentioning

confidence: 99%

Retromer- and WASH-dependent sorting of nutrient transporters requires a multivalent interaction network with ANKRD50

Kvainickas

Orgaz

Nägele

et al. 2017

Journal of Cell Science

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Retromer and the associated actin-polymerizing WASH complex are essential for the endocytic recycling of a wide range of integral membrane proteins. A hereditary Parkinson's-disease-causing point mutation (D620N) in the retromer subunit VPS35 perturbs retromer's association with the WASH complex and also with the uncharacterized protein ankyrin-repeat-domain-containing protein 50 (ANKRD50). Here, we firmly establish ANKRD50 as a new and essential component of the SNX27-retromer-WASH super complex. Depletion of ANKRD50 in HeLa or U2OS cells phenocopied the loss of endosome-to-cell-surface recycling of multiple transmembrane proteins seen upon suppression of SNX27, retromer or WASHcomplex components. Mass-spectrometry-based quantification of the cell surface proteome of ANKRD50-depleted cells identified amino acid transporters of the SLC1A family, among them SLC1A4, as additional cargo molecules that depend on ANKRD50 and retromer for their endocytic recycling. Mechanistically, we show that ANKRD50 simultaneously engages multiple parts of the SNX27-retromer-WASH complex machinery in a direct and co-operative interaction network that is needed to efficiently recycle the nutrient transporters GLUT1 (also known as SLC2A1) and SLC1A4, and potentially many other surface proteins.

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Sorting nexin 27 couples PTHR trafficking to retromer for signal regulation in osteoblasts during bone growth

Cited by 49 publications

References 85 publications

Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling

Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling

GPCR Signaling and Trafficking: The Long and Short of It

Retromer- and WASH-dependent sorting of nutrient transporters requires a multivalent interaction network with ANKRD50

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