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

Authors
 Jia Rao  ;  Shazia Ashraf  ;  Weizhen Tan  ;  Amelie T. van der Ven  ;  Heon Yung Gee  ;  Daniela A. Braun  ;  Krisztina Fehér  ;  Sudeep P. George  ;  Amin Esmaeilniakooshkghazi  ;  Won-Il Choi  ;  Tilman Jobst-Schwan  ;  Ronen Schneider  ;  Johanna Magdalena Schmidt  ;  Eugen Widmeier  ;  Jillian K. Warejko  ;  Tobias Hermle  ;  David Schapiro  ;  Svjetlana Lovric  ;  Shirlee Shril  ;  Ankana Daga  ;  Ahmet Nayir  ;  Mohan Shenoy  ;  Yincent Tse  ;  Martin Bald  ;  Udo Helmchen  ;  Sevgi Mir  ;  Afig Berdeli  ;  Jameela A. Kari  ;  Sherif El Desoky  ;  Neveen A. Soliman  ;  Arvind Bagga  ;  Shrikant Mane  ;  Mohamad A. Jairajpuri  ;  Richard P. Lifton  ;  Seema Khurana  ;  Jose C. Martins  ;  Friedhelm Hildebrandt 
Citation
 Journal of Clinical Investigation, Vol.127(12) : 4257-4269, 2017 
Journal Title
 Journal of Clinical Investigation 
ISSN
 0021-9738 
Issue Date
2017
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.
Files in This Item:
T201705740.pdf Download
DOI
10.1172/JCI94138
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/161747
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