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

TitleAdvillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.
Publication TypeJournal Article
Year of Publication2017
AuthorsRao, J, Ashraf, S, Tan, W, van der Ven, AT, Gee, HYung, Braun, DA, Fehér, K, George, SP, Esmaeilniakooshkghazi, A, Choi, W-I, Jobst-Schwan, T, Schneider, R, Schmidt, JMagdalena, 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, Desoky, SEl, Soliman, NA, Bagga, A, Mane, S, Jairajpuri, MA, Lifton, RP, Khurana, S, Martins, JC, Hildebrandt, F
JournalJ Clin Invest
Date Published2017 12 01
KeywordsActin-Related Protein 2-3 Complex, Cell Movement, Diglycerides, Female, Humans, Male, Microfilament Proteins, Mutation, Nephrotic Syndrome, Phosphoinositide Phospholipase C, Podocytes, Pseudopodia

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.

Alternate JournalJ. Clin. Invest.
PubMed ID29058690
PubMed Central IDPMC5707164
Grant ListR01 DK098120 / DK / NIDDK NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
S10 OD018521 / OD / NIH HHS / United States
R01 DK076683 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
P30 DK056338 / DK / NIDDK NIH HHS / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States