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

J Clin Invest. 2017 Dec 1;127(12):4257-4269. doi: 10.1172/JCI94138.

Jia Rao ¹ ², Shazia Ashraf ¹ ³, Weizhen Tan ¹, Amelie T van der Ven ¹, Heon Yung Gee ¹ ⁴, Daniela A Braun ¹, Krisztina Fehér ⁵, Sudeep P George ⁶, Amin Esmaeilniakooshkghazi ⁶, Won-Il Choi ¹, Tilman Jobst-Schwan ¹, Ronen Schneider ¹, Johanna Magdalena Schmidt ¹, Eugen Widmeier ¹, Jillian K Warejko ¹, Tobias Hermle ¹, David Schapiro ¹, Svjetlana Lovric ¹, Shirlee Shril ¹, Ankana Daga ¹, Ahmet Nayir ⁷, Mohan Shenoy ⁸, Yincent Tse ⁹, Martin Bald ¹⁰, Udo Helmchen ¹¹, Sevgi Mir ¹², Afig Berdeli ¹², Jameela A Kari ¹³, Sherif El Desoky ¹³, Neveen A Soliman ¹⁴, Arvind Bagga ¹⁵, Shrikant Mane ¹⁶, Mohamad A Jairajpuri ³, Richard P Lifton ¹⁶ ¹⁷, Seema Khurana ⁶ ¹⁸, Jose C Martins ⁵, Friedhelm Hildebrandt ¹

Affiliations

1 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2 Department of Medicine, Nephrology, Children's Hospital of Fudan University, Shanghai, China.
3 Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
4 Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
5 NMR and Structure Analysis Group, Department of Organic and Macromolecular Chemistry, University of Gent, Gent, Belgium.
6 Department of Biology and Biochemistry, University of Houston, Houston,Texas, USA.
7 Department of Pediatric Nephrology, Faculty of Medicine, University of Istanbul, Istanbul, Turkey.
8 Department of Pediatric Nephrology, Royal Manchester Children's Hospital, Manchester, United Kingdom.
9 Department of Pediatric Nephrology, Great North Children's Hospital, Newcastle Upon Tyne, United Kingdom.
10 Olga Children's Hospital, Clinic Stuttgart, Stuttgart, Germany.
11 Institute of Pathology, Kidney Registry, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
12 Department of Pediatrics, Molecular Medicine Laboratory, Ege University, Izmir, Turkey.
13 Pediatric Nephrology Center of Excellence and Pediatric Department, King Abdulaziz University, Jeddah, Saudi Arabia.
14 Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt.
15 Division of Pediatric Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
16 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
17 Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
18 Baylor College of Medicine, Houston, Texas, USA.

PMID: 29058690 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.

Keywords

Monogenic diseases; Nephrology.

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