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

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 DagaAhmet 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)4257-4269
Number of pages13
JournalJournal of Clinical Investigation
Volume127
Issue number12
DOIs
Publication statusPublished - 2017 Dec 1

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Nephrotic Syndrome
Type C Phospholipases
Podocytes
Actins
Steroids
Pseudopodia
Epidermal Growth Factor
Pheniramine
Microfilament Proteins
Stress Fibers
Mutation
Aptitude
Phospholipases
Diglycerides
Chronic Renal Insufficiency
Enzymes
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

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
Rao, Jia ; Ashraf, Shazia ; Tan, Weizhen ; Van Der Ven, Amelie T. ; Gee, Heon Yung ; Braun, Daniela A. ; Fehér, Krisztina ; George, Sudeep P. ; Esmaeilniakooshkghazi, Amin ; Choi, Won Il ; Jobst-Schwan, Tilman ; Schneider, Ronen ; Schmidt, Johanna Magdalena ; Widmeier, Eugen ; Warejko, Jillian K. ; Hermle, Tobias ; Schapiro, David ; Lovric, Svjetlana ; Shril, Shirlee ; Daga, Ankana ; Nayir, Ahmet ; Shenoy, Mohan ; Tse, Yincent ; Bald, Martin ; Helmchen, Udo ; Mir, Sevgi ; Berdeli, Afig ; Kari, Jameela A. ; El Desoky, Sherif ; Soliman, Neveen A. ; Bagga, Arvind ; Mane, Shrikant ; Jairajpuri, Mohamad A. ; Lifton, Richard P. ; Khurana, Seema ; Martins, Jose C. ; Hildebrandt, Friedhelm. / Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 12. pp. 4257-4269.
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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.",
author = "Jia Rao and Shazia Ashraf and Weizhen Tan and {Van Der Ven}, {Amelie T.} and Gee, {Heon Yung} and Braun, {Daniela A.} and Krisztina Feh{\'e}r and George, {Sudeep P.} and Amin Esmaeilniakooshkghazi and Choi, {Won Il} and Tilman Jobst-Schwan and Ronen Schneider and Schmidt, {Johanna Magdalena} and Eugen Widmeier and Warejko, {Jillian K.} and Tobias Hermle and David Schapiro and Svjetlana Lovric and Shirlee Shril and Ankana Daga and Ahmet Nayir and Mohan Shenoy and Yincent Tse and Martin Bald and Udo Helmchen and Sevgi Mir and Afig Berdeli and Kari, {Jameela A.} and {El Desoky}, Sherif and Soliman, {Neveen A.} and Arvind Bagga and Shrikant Mane and Jairajpuri, {Mohamad A.} and Lifton, {Richard P.} and Seema Khurana and Martins, {Jose C.} and Friedhelm Hildebrandt",
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Rao, J, Ashraf, S, Tan, W, Van Der Ven, AT, Gee, HY, Braun, DA, Fehér, 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, 'Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome', Journal of Clinical Investigation, vol. 127, no. 12, pp. 4257-4269. https://doi.org/10.1172/JCI94138

Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome. / Rao, Jia; Ashraf, Shazia; Tan, Weizhen; Van Der Ven, Amelie T.; Gee, Heon Yung; Braun, Daniela A.; Fehér, Krisztina; George, Sudeep P.; Esmaeilniakooshkghazi, Amin; Choi, Won Il; Jobst-Schwan, Tilman; Schneider, Ronen; Schmidt, Johanna Magdalena; Widmeier, Eugen; Warejko, Jillian K.; Hermle, Tobias; Schapiro, David; Lovric, Svjetlana; Shril, Shirlee; Daga, Ankana; Nayir, Ahmet; Shenoy, Mohan; Tse, Yincent; Bald, Martin; Helmchen, Udo; Mir, Sevgi; Berdeli, Afig; Kari, Jameela A.; El Desoky, Sherif; Soliman, Neveen A.; Bagga, Arvind; Mane, Shrikant; Jairajpuri, Mohamad A.; Lifton, Richard P.; Khurana, Seema; Martins, Jose C.; Hildebrandt, Friedhelm.

In: Journal of Clinical Investigation, Vol. 127, No. 12, 01.12.2017, p. 4257-4269.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome

AU - Rao, Jia

AU - Ashraf, Shazia

AU - Tan, Weizhen

AU - Van Der Ven, Amelie T.

AU - Gee, Heon Yung

AU - Braun, Daniela A.

AU - Fehér, Krisztina

AU - George, Sudeep P.

AU - Esmaeilniakooshkghazi, Amin

AU - Choi, Won Il

AU - Jobst-Schwan, Tilman

AU - Schneider, Ronen

AU - Schmidt, Johanna Magdalena

AU - Widmeier, Eugen

AU - Warejko, Jillian K.

AU - Hermle, Tobias

AU - Schapiro, David

AU - Lovric, Svjetlana

AU - Shril, Shirlee

AU - Daga, Ankana

AU - Nayir, Ahmet

AU - Shenoy, Mohan

AU - Tse, Yincent

AU - Bald, Martin

AU - Helmchen, Udo

AU - Mir, Sevgi

AU - Berdeli, Afig

AU - Kari, Jameela A.

AU - El Desoky, Sherif

AU - Soliman, Neveen A.

AU - Bagga, Arvind

AU - Mane, Shrikant

AU - Jairajpuri, Mohamad A.

AU - Lifton, Richard P.

AU - Khurana, Seema

AU - Martins, Jose C.

AU - Hildebrandt, Friedhelm

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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