title: Deficiency of sorting nexin 27 (SNX27) leads to growth retardation and elevated levels of N-methyl-D-aspartate receptor 2C (NR2C).
abstract: Phox (PX) domain-containing sorting nexins (SNXs) are emerging as important regulators of endocytic trafficking. Sorting nexin 27 (SNX27) is unique, as it contains a PDZ (Psd-95/Dlg/ZO1) domain. We show here that SNX27 is primarily targeted to the early endosome by interaction of its PX domain with PtdIns(3)P. Although targeted ablation of the SNX27 gene in mice did not significantly affect growth and survival during embryonic development, SNX27 plays an essential role in postnatal growth and survival. N-Methyl-d-aspartate (NMDA) receptor 2C (NR2C) was identified as a novel SNX27-interacting protein, and this interaction is mediated by the PDZ domain of SNX27 and the C-terminal PDZ-binding motif of NR2C. Increased NR2C expression levels, together with impaired NR2C endocytosis in SNX27(-/-) neurons, indicate that SNX27 may function to regulate endocytosis and/or endosomal sorting of NR2C. This is consistent with a role of SNX27 as a general regulator for sorting of membrane proteins containing a PDZ-binding motif, and its absence may alter the trafficking of these proteins, leading to growth and survival defects.
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.forename: Li Shen
authors.initials: LS
authors.lastname: Loo
authors.forename: Vadim
authors.initials: V
authors.lastname: Atlashkin
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Hanson
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D058305:Sorting Nexins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C432823:NR2C NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C522885:SNX27 protein, human; C500393:Snx27 protein, mouse; D058305:Sorting Nexins; D019869:Phosphatidylinositol 3-Kinases