Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome

Rao J, Ashraf S, Tan W, Van Der Ven AT, Gee HY, Braun DA, Feher K, George SP, Esmaeilniakooshkghazi A, Choi WI, Jobst-Schwan T, Schneider R, Schmidt JM, Widmeier E, Warejko JK, Hermle T, Schapiro D, Lovric S, Shril S, Daga A, Nayir A, Shenoy M, Tse Y, Bald M, Helmchen U, Mir S, Berdeli A, Kari JA, El Desoky S, Soliman NA, Bagga A, Mane S, Jairajpuri MA, Lifton RP, Khurana S, Martins JC, Hildebrandt F (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 127

Pages Range: 4257-4269

Journal Issue: 12

DOI: 10.1172/JCI94138

Abstract

Steroid-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.

Authors with CRIS profile

Tilman Jobst-Schwan

Involved external institutions

Harvard University US United States (USA) (US) Ege University / Ege Üniversitesi TR Turkey (TR) Yale University US United States (USA) (US) Cairo University EG Egypt (EG) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) King Abdulaziz University (KAU) / جامعة الملك عبد العزيز SA Saudi Arabia (SA) University of Houston US United States (USA) (US) Universiteit Gent (UGent) / Ghent University BE Belgium (BE) Klinikum Stuttgart DE Germany (DE) Istanbul University / İstanbul Üniversitesi TR Turkey (TR) Great North Children's Hospital GB United Kingdom (GB) Jamia Millia Islamia IN India (IN) All India Institute of Medical Sciences IN India (IN) Royal Manchester Children's Hospital GB United Kingdom (GB)

How to cite

APA:

Rao, J., Ashraf, S., Tan, W., Van Der Ven, A.T., Gee, H.Y., Braun, D.A.,... Hildebrandt, F. (2017). Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome. Journal of Clinical Investigation, 127(12), 4257-4269. https://doi.org/10.1172/JCI94138

MLA:

Rao, Jia, et al. "Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome." Journal of Clinical Investigation 127.12 (2017): 4257-4269.

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