Advillin acts upstream of phospholipase C ?1 in steroid-resistant nephrotic syndrome

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dc.contributor.authorRao J.
dc.contributor.authorAshraf S.
dc.contributor.authorTan W.
dc.contributor.authorVan Der Ven A.T.
dc.contributor.authorGee H.Y.
dc.contributor.authorBraun D.A.
dc.contributor.authorFehér K.
dc.contributor.authorGeorge S.P.
dc.contributor.authorEsmaeilniakooshkghazi A.
dc.contributor.authorChoi W.-I.
dc.contributor.authorJobst-Schwan T.
dc.contributor.authorSchneider R.
dc.contributor.authorSchmidt J.M.
dc.contributor.authorWidmeier E.
dc.contributor.authorWarejko J.K.
dc.contributor.authorHermle T.
dc.contributor.authorSchapiro D.
dc.contributor.authorLovric S.
dc.contributor.authorShril S.
dc.contributor.authorDaga A.
dc.contributor.authorNayir A.
dc.contributor.authorShenoy M.
dc.contributor.authorTse Y.
dc.contributor.authorBald M.
dc.contributor.authorHelmchen U.
dc.contributor.authorMir S.
dc.contributor.authorBerdeli A.
dc.contributor.authorKari J.A.
dc.contributor.authorEl Desoky S.
dc.contributor.authorSoliman N.A.
dc.contributor.authorBagga A.
dc.contributor.authorMane S.
dc.contributor.authorJairajpuri M.A.
dc.contributor.authorLifton R.P.
dc.contributor.authorKhurana S.
dc.contributor.authorMartins J.C.
dc.contributor.authorHildebrandt F.
dc.date.accessioned2019-10-27T08:03:23Z
dc.date.available2019-10-27T08:03:23Z
dc.date.issued2017
dc.departmentEge Üniversitesien_US
dc.description.abstractSteroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avil or PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein.en_US
dc.description.sponsorshipVE 196/1-1, HE 7456/1-1, Jo 1324/1-1 U.S. Public Health Service: DK-56338 National Institutes of Health: DK076683 National Institute of Diabetes and Digestive and Kidney Diseases: DK-98120 National Research Foundation of Korea, NRF: 2015R1D1A1A01056685 Department of Science and Technology, Government of Kerala NAS LPDS-2015-07 Fudan Universityen_US
dc.description.sponsorshipWe are grateful to the families and study participants for their contributions. We thank the Yale Center for Mendelian Genomics (U54HG006504) for WES analysis. FH is a William E. Harmon Professor of Pediatrics. This research was supported by the NIH (DK076683, to FH); the Young Scholars Program of Children’s Hospital of Fudan University (to JR); Basic Science Research Program through the National Research Foundation of Korea 2015R1D1A1A01056685 (to HYG); DFG fellowships (VE 196/1-1, to ATvdV; Jo 1324/1-1, to TJS; and HE 7456/1-1, to TH); the German National Academy of Sciences Leopoldina (LPDS-2015-07, to EW); the Egyptian Group for Orphan Renal Diseases (EGORD) (to NAS); the Department of Science and Technology, Government of India (DST-SERB, to MAJ); the National Institute of Diabetes and Digestive and Kidney Diseases (DK-98120, to SK); and the Public Health Service (DK-56338, to SK). --en_US
dc.identifier.doi10.1172/JCI94138en_US
dc.identifier.endpage4269en_US
dc.identifier.issn0021-9738
dc.identifier.issue12en_US
dc.identifier.pmid29058690en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage4257en_US
dc.identifier.urihttps://doi.org/10.1172/JCI94138
dc.identifier.urihttps://hdl.handle.net/11454/25349
dc.identifier.volume127en_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.ispartofJournal of Clinical Investigationen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleAdvillin acts upstream of phospholipase C ?1 in steroid-resistant nephrotic syndromeen_US
dc.typeArticleen_US

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