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 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

doi:10.1172/JCI94138

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

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

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 language	English
Pages (from-to)	4257-4269
Number of pages	13
Journal	Journal of Clinical Investigation
Volume	127
Issue number	12
DOIs	https://doi.org/10.1172/JCI94138
Publication status	Published - 2017 Dec 1

Bibliographical note

Funding Information:
We are grateful to the families and study participants for their contributions. We thank the Yale Center for Mendelian Genomics (U54HG006504) for WES analysis. FH is a William E. Harmon Professor of Pediatrics. This research was supported by the NIH (DK076683, to FH); the Young Scholars Program of Children’s Hospital of Fudan University (to JR); Basic Science Research Program through the National Research Foundation of Korea 2015R1D1A1A01056685 (to HYG); DFG fellowships (VE 196/1-1, to ATvdV; Jo 1324/1-1, to TJS; and HE 7456/1-1, to TH); the German National Academy of Sciences Leopoldina (LPDS-2015-07, to EW); the Egyptian Group for Orphan Renal Diseases (EGORD) (to NAS); the Department of Science and Technology, Government of India (DST-SERB, to MAJ); the National Institute of Diabetes and Digestive and Kidney Diseases (DK-98120, to SK); and the Public Health Service (DK-56338, to SK).

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Medicine(all)

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10.1172/JCI94138

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Rao, J., Ashraf, S., Tan, W., Van Der Ven, A. T., Gee, H. Y., Braun, D. A., Fehér, K., George, S. P., Esmaeilniakooshkghazi, A., Choi, W. I., Jobst-Schwan, T., Schneider, R., Schmidt, J. M., Widmeier, E., Warejko, J. K., Hermle, T., Schapiro, D., Lovric, S., Shril, S., ... 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

@article{b9759f25e86e46488fd44739e3e49ee6,

title = "Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome",

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",

note = "Funding Information: We are grateful to the families and study participants for their contributions. We thank the Yale Center for Mendelian Genomics (U54HG006504) for WES analysis. FH is a William E. Harmon Professor of Pediatrics. This research was supported by the NIH (DK076683, to FH); the Young Scholars Program of Children{\textquoteright}s Hospital of Fudan University (to JR); Basic Science Research Program through the National Research Foundation of Korea 2015R1D1A1A01056685 (to HYG); DFG fellowships (VE 196/1-1, to ATvdV; Jo 1324/1-1, to TJS; and HE 7456/1-1, to TH); the German National Academy of Sciences Leopoldina (LPDS-2015-07, to EW); the Egyptian Group for Orphan Renal Diseases (EGORD) (to NAS); the Department of Science and Technology, Government of India (DST-SERB, to MAJ); the National Institute of Diabetes and Digestive and Kidney Diseases (DK-98120, to SK); and the Public Health Service (DK-56338, to SK).",

year = "2017",

month = dec,

day = "1",

doi = "10.1172/JCI94138",

language = "English",

volume = "127",

pages = "4257--4269",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "12",

}

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

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

N1 - Funding Information: We are grateful to the families and study participants for their contributions. We thank the Yale Center for Mendelian Genomics (U54HG006504) for WES analysis. FH is a William E. Harmon Professor of Pediatrics. This research was supported by the NIH (DK076683, to FH); the Young Scholars Program of Children’s Hospital of Fudan University (to JR); Basic Science Research Program through the National Research Foundation of Korea 2015R1D1A1A01056685 (to HYG); DFG fellowships (VE 196/1-1, to ATvdV; Jo 1324/1-1, to TJS; and HE 7456/1-1, to TH); the German National Academy of Sciences Leopoldina (LPDS-2015-07, to EW); the Egyptian Group for Orphan Renal Diseases (EGORD) (to NAS); the Department of Science and Technology, Government of India (DST-SERB, to MAJ); the National Institute of Diabetes and Digestive and Kidney Diseases (DK-98120, to SK); and the Public Health Service (DK-56338, to SK).

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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DO - 10.1172/JCI94138

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AN - SCOPUS:85037101103

SN - 0021-9738

VL - 127

SP - 4257

EP - 4269

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 12

ER -

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

Abstract

Bibliographical note

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UN SDGs

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