Phosphorylation of PACSIN2 at S313 Regulates Podocyte Architecture in Coordination with N-WASP

Rim Bouslama; Vincent Dumont; Sonja Lindfors; Lassi Paavolainen; Jukka Tienari; Harry Nisen; Tuomas Mirtti; Moin A Saleem; Daniel Gordin; Per-Henrik Groop; Shiro Suetsugu; Sanna Lehtonen

doi:10.3390/cells12111487

Phosphorylation of PACSIN2 at S313 Regulates Podocyte Architecture in Coordination with N-WASP

Rim Bouslama, Vincent Dumont, Sonja Lindfors, Lassi Paavolainen, Jukka Tienari, Harry Nisen, Tuomas Mirtti, Moin A Saleem, Daniel Gordin, Per-Henrik Groop, Shiro Suetsugu, Sanna Lehtonen^*

^*Corresponding author for this work

Bristol Medical School (THS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

Abstract

Changes in the dynamic architecture of podocytes, the glomerular epithelial cells, lead to kidney dysfunction. Previous studies on protein kinase C and casein kinase 2 substrates in neurons 2 (PACSIN2), a known regulator of endocytosis and cytoskeletal organization, reveal a connection between PACSIN2 and kidney pathogenesis. Here, we show that the phosphorylation of PACSIN2 at serine 313 (S313) is increased in the glomeruli of rats with diabetic kidney disease. We found that phosphorylation at S313 is associated with kidney dysfunction and increased free fatty acids rather than with high glucose and diabetes alone. Phosphorylation of PACSIN2 emerged as a dynamic process that fine-tunes cell morphology and cytoskeletal arrangement, in cooperation with the regulator of the actin cytoskeleton, Neural Wiskott-Aldrich syndrome protein (N-WASP). PACSIN2 phosphorylation decreased N-WASP degradation while N-WASP inhibition triggered PACSIN2 phosphorylation at S313. Functionally, pS313-PACSIN2 regulated actin cytoskeleton rearrangement depending on the type of cell injury and the signaling pathways involved. Collectively, this study indicates that N-WASP induces phosphorylation of PACSIN2 at S313, which serves as a mechanism whereby cells regulate active actin-related processes. The dynamic phosphorylation of S313 is needed to regulate cytoskeletal reorganization.

Original language	English
Article number	1487
Journal	Cells
Volume	12
Issue number	11
DOIs	https://doi.org/10.3390/cells12111487
Publication status	Published - 27 May 2023

Bibliographical note

Funding Information:
This work was supported by grants from the Doctoral Programme in Biomedicine (to RB) and Finnish Diabetes Research Foundation (Diabetestutkimussäätiö, to RB, VD and SoL), Finnish Kidney Foundation (Munuaissäätiö, to RB, VD and SoL), Onni and Hilja Tuovinen Foundation (to RB), Finnish-Norwegian Medical Research Foundation (to SoL), Jalmari and Rauha Ahokas Foundation (to RB and VD), Orion Foundation (to VD), Alfred Kordelin Foundation (to VD), Maud Kuistila Foundation (to VD), HiLife, University of Helsinki (to SaL, DG), Sigrid Jusélius Foundation (to SaL, DG), Päivikki and Sakari Sohlberg Foundation (to SoL, DG), Liv och Hälsa Society (to DG), Medical Society of Finland (Finska Läkaresällskapet, to DG), Academy of Finland (1219001, to DG; 310552, to LP), Wilhelm and Else Stockmann Foundation (to DG), EVO governmental grants (to DG), Perklén Foundation (to DG), University of Helsinki (Clinical Researcher stint, to DG), Hospital District of Helsinki and Uusimaa (TYH2018235, to TM), and Finnish Medical Foundation (to TM).

Publisher Copyright:
© 2023 by the authors.

Keywords

Rats
Animals
Phosphorylation
Caseins/metabolism
Podocytes/metabolism
Serine/metabolism
Neurons/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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@article{6440e8e1664849ee85056dc5cb7041f4,

title = "Phosphorylation of PACSIN2 at S313 Regulates Podocyte Architecture in Coordination with N-WASP",

abstract = "Changes in the dynamic architecture of podocytes, the glomerular epithelial cells, lead to kidney dysfunction. Previous studies on protein kinase C and casein kinase 2 substrates in neurons 2 (PACSIN2), a known regulator of endocytosis and cytoskeletal organization, reveal a connection between PACSIN2 and kidney pathogenesis. Here, we show that the phosphorylation of PACSIN2 at serine 313 (S313) is increased in the glomeruli of rats with diabetic kidney disease. We found that phosphorylation at S313 is associated with kidney dysfunction and increased free fatty acids rather than with high glucose and diabetes alone. Phosphorylation of PACSIN2 emerged as a dynamic process that fine-tunes cell morphology and cytoskeletal arrangement, in cooperation with the regulator of the actin cytoskeleton, Neural Wiskott-Aldrich syndrome protein (N-WASP). PACSIN2 phosphorylation decreased N-WASP degradation while N-WASP inhibition triggered PACSIN2 phosphorylation at S313. Functionally, pS313-PACSIN2 regulated actin cytoskeleton rearrangement depending on the type of cell injury and the signaling pathways involved. Collectively, this study indicates that N-WASP induces phosphorylation of PACSIN2 at S313, which serves as a mechanism whereby cells regulate active actin-related processes. The dynamic phosphorylation of S313 is needed to regulate cytoskeletal reorganization.",

keywords = "Rats, Animals, Phosphorylation, Caseins/metabolism, Podocytes/metabolism, Serine/metabolism, Neurons/metabolism",

author = "Rim Bouslama and Vincent Dumont and Sonja Lindfors and Lassi Paavolainen and Jukka Tienari and Harry Nisen and Tuomas Mirtti and Saleem, {Moin A} and Daniel Gordin and Per-Henrik Groop and Shiro Suetsugu and Sanna Lehtonen",

note = "Funding Information: This work was supported by grants from the Doctoral Programme in Biomedicine (to RB) and Finnish Diabetes Research Foundation (Diabetestutkimuss{\"a}{\"a}ti{\"o}, to RB, VD and SoL), Finnish Kidney Foundation (Munuaiss{\"a}{\"a}ti{\"o}, to RB, VD and SoL), Onni and Hilja Tuovinen Foundation (to RB), Finnish-Norwegian Medical Research Foundation (to SoL), Jalmari and Rauha Ahokas Foundation (to RB and VD), Orion Foundation (to VD), Alfred Kordelin Foundation (to VD), Maud Kuistila Foundation (to VD), HiLife, University of Helsinki (to SaL, DG), Sigrid Jus{\'e}lius Foundation (to SaL, DG), P{\"a}ivikki and Sakari Sohlberg Foundation (to SoL, DG), Liv och H{\"a}lsa Society (to DG), Medical Society of Finland (Finska L{\"a}kares{\"a}llskapet, to DG), Academy of Finland (1219001, to DG; 310552, to LP), Wilhelm and Else Stockmann Foundation (to DG), EVO governmental grants (to DG), Perkl{\'e}n Foundation (to DG), University of Helsinki (Clinical Researcher stint, to DG), Hospital District of Helsinki and Uusimaa (TYH2018235, to TM), and Finnish Medical Foundation (to TM). Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = may,

day = "27",

doi = "10.3390/cells12111487",

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T1 - Phosphorylation of PACSIN2 at S313 Regulates Podocyte Architecture in Coordination with N-WASP

AU - Bouslama, Rim

AU - Dumont, Vincent

AU - Lindfors, Sonja

AU - Paavolainen, Lassi

AU - Tienari, Jukka

AU - Nisen, Harry

AU - Mirtti, Tuomas

AU - Saleem, Moin A

AU - Gordin, Daniel

AU - Groop, Per-Henrik

AU - Suetsugu, Shiro

AU - Lehtonen, Sanna

N1 - Funding Information: This work was supported by grants from the Doctoral Programme in Biomedicine (to RB) and Finnish Diabetes Research Foundation (Diabetestutkimussäätiö, to RB, VD and SoL), Finnish Kidney Foundation (Munuaissäätiö, to RB, VD and SoL), Onni and Hilja Tuovinen Foundation (to RB), Finnish-Norwegian Medical Research Foundation (to SoL), Jalmari and Rauha Ahokas Foundation (to RB and VD), Orion Foundation (to VD), Alfred Kordelin Foundation (to VD), Maud Kuistila Foundation (to VD), HiLife, University of Helsinki (to SaL, DG), Sigrid Jusélius Foundation (to SaL, DG), Päivikki and Sakari Sohlberg Foundation (to SoL, DG), Liv och Hälsa Society (to DG), Medical Society of Finland (Finska Läkaresällskapet, to DG), Academy of Finland (1219001, to DG; 310552, to LP), Wilhelm and Else Stockmann Foundation (to DG), EVO governmental grants (to DG), Perklén Foundation (to DG), University of Helsinki (Clinical Researcher stint, to DG), Hospital District of Helsinki and Uusimaa (TYH2018235, to TM), and Finnish Medical Foundation (to TM). Publisher Copyright: © 2023 by the authors.

PY - 2023/5/27

Y1 - 2023/5/27

N2 - Changes in the dynamic architecture of podocytes, the glomerular epithelial cells, lead to kidney dysfunction. Previous studies on protein kinase C and casein kinase 2 substrates in neurons 2 (PACSIN2), a known regulator of endocytosis and cytoskeletal organization, reveal a connection between PACSIN2 and kidney pathogenesis. Here, we show that the phosphorylation of PACSIN2 at serine 313 (S313) is increased in the glomeruli of rats with diabetic kidney disease. We found that phosphorylation at S313 is associated with kidney dysfunction and increased free fatty acids rather than with high glucose and diabetes alone. Phosphorylation of PACSIN2 emerged as a dynamic process that fine-tunes cell morphology and cytoskeletal arrangement, in cooperation with the regulator of the actin cytoskeleton, Neural Wiskott-Aldrich syndrome protein (N-WASP). PACSIN2 phosphorylation decreased N-WASP degradation while N-WASP inhibition triggered PACSIN2 phosphorylation at S313. Functionally, pS313-PACSIN2 regulated actin cytoskeleton rearrangement depending on the type of cell injury and the signaling pathways involved. Collectively, this study indicates that N-WASP induces phosphorylation of PACSIN2 at S313, which serves as a mechanism whereby cells regulate active actin-related processes. The dynamic phosphorylation of S313 is needed to regulate cytoskeletal reorganization.

AB - Changes in the dynamic architecture of podocytes, the glomerular epithelial cells, lead to kidney dysfunction. Previous studies on protein kinase C and casein kinase 2 substrates in neurons 2 (PACSIN2), a known regulator of endocytosis and cytoskeletal organization, reveal a connection between PACSIN2 and kidney pathogenesis. Here, we show that the phosphorylation of PACSIN2 at serine 313 (S313) is increased in the glomeruli of rats with diabetic kidney disease. We found that phosphorylation at S313 is associated with kidney dysfunction and increased free fatty acids rather than with high glucose and diabetes alone. Phosphorylation of PACSIN2 emerged as a dynamic process that fine-tunes cell morphology and cytoskeletal arrangement, in cooperation with the regulator of the actin cytoskeleton, Neural Wiskott-Aldrich syndrome protein (N-WASP). PACSIN2 phosphorylation decreased N-WASP degradation while N-WASP inhibition triggered PACSIN2 phosphorylation at S313. Functionally, pS313-PACSIN2 regulated actin cytoskeleton rearrangement depending on the type of cell injury and the signaling pathways involved. Collectively, this study indicates that N-WASP induces phosphorylation of PACSIN2 at S313, which serves as a mechanism whereby cells regulate active actin-related processes. The dynamic phosphorylation of S313 is needed to regulate cytoskeletal reorganization.

KW - Rats

KW - Animals

KW - Phosphorylation

KW - Caseins/metabolism

KW - Podocytes/metabolism

KW - Serine/metabolism

KW - Neurons/metabolism

U2 - 10.3390/cells12111487

DO - 10.3390/cells12111487

M3 - Article (Academic Journal)

C2 - 37296607

SN - 2073-4409

VL - 12

JO - Cells

JF - Cells

IS - 11

M1 - 1487

ER -

Phosphorylation of PACSIN2 at S313 Regulates Podocyte Architecture in Coordination with N-WASP

Abstract

Bibliographical note

Keywords

UN SDGs

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