Acetyl-NPKY of integrin-β1 binds KINDLIN2 to control endothelial cell proliferation and junctional integrity

Adama Sidibé; Vasyl V. Mykuliak; Pingfeng Zhang; Vesa P. Hytönen; Jinhua Wu; Bernhard Wehrle-Haller

doi:10.1016/j.isci.2024.110129

Acetyl-NPKY of integrin-β1 binds KINDLIN2 to control endothelial cell proliferation and junctional integrity

Adama Sidibé^*
, Vasyl V. Mykuliak
, Pingfeng Zhang
, Vesa P. Hytönen
, Jinhua Wu
, Bernhard Wehrle-Haller^*

^*Tämän työn vastaava kirjoittaja

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

6 Sitaatiot (Scopus)

45 Lataukset (Pure)

Abstrakti

Integrin-dependent crosstalk between cell-matrix adhesions and cell-cell junctions is critical for controlling endothelial permeability and proliferation in cancer and inflammatory diseases but remains poorly understood. Here, we investigated how acetylation of the distal NPKY-motif of Integrin-β1 influences endothelial cell physiology and barrier function. Expression of an acetylation-mimetic β1-K794Q-GFP mutant led to the accumulation of immature cell-matrix adhesions accompanied by a transcriptomic reprograming of endothelial cells, involving genes associated with cell adhesion, proliferation, polarity, and barrier function. β1-K794Q-GFP induced constitutive MAPK signaling, junctional impairment, proliferation, and reduced contact inhibition at confluence. Structural analysis of Integrin-β1 interaction with KINDLIN2, biochemical pulldown assay, and binding energy determination by using molecular dynamics simulation showed that acetylation of K794 and the K794Q-mutant increased KINDLIN2 binding affinity to the Integrin-β1. Thus, enhanced recruitment of KINDLIN2 to Lysine-acetylated Integrin-β1 and resulting modulation of barrier function, offers new therapeutic possibilities for controlling vascular permeability and disease conditions.

Alkuperäiskieli	Englanti
Artikkeli	110129
Julkaisu	iScience
Vuosikerta	27
Numero	6
DOI - pysyväislinkit	https://doi.org/10.1016/j.isci.2024.110129
Tila	Julkaistu - 21 kesäk. 2024
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Rahoitus

This work benefited financially from grants from the Sir Jules Thorn Charitable Overseas Trust Reg (to A.S.), Gertrude von Meissner Foundation (to A.S. and B.W.H.), Geneva Cancer Foundation (to A.S. and B.W.H.), Dinu Lipatti Foundation (to A.S. and B.W.H.) and the Swiss National Science Foundation (310030-185261 to B.W.H). A.S. was recipient of fellowship for Ma\u00EEtre-Assistant of the Faculty of Medicine of University of Geneva. We thank the core facilities of the Faculty of Medicine of University of Geneva including the Genomic, Flow cytometry and Bioimaging core facilities. We are grateful to St\u00E9phane Konig, Katharina Rickenbach, Monica Julio Barreto, Patricia Ropraz, Christelle Barraclough, Didier Chollet and C\u00E9line Delucinge-Vivier for technical supports. V.V.M. acknowledges support by the Academy of Finland (grant 323021). V.H. acknowledges support by Sigrid Juselius Foundation and Cancer Foundation Finland. We acknowledge CSC \u2013 IT Center for Science for computational resources. Part of this work was supported by an NIH Grant GM119560 (to J.W.), an ASH Bridge Grant (to J.W.), and an ACS Grant RSG-15-167-01-DMC (to J.W.). Conceptualization: A.S. and B.W.-H.; methodology: A.S. V.V.M. P.Z. V.P.H. J.W. and B.W.-H.; investigation: A.S. V.M. P.Z. V.H. J.W. and B.W.-H.; writing \u2013 drafting and editing: A.S. V.M. P.Z. V.H. J.W. and B.W.-H. The authors declare no competing financial interests.

Rahoittajat	Rahoittajan numero
Gertrude von Meissner-Stiftung
Faculty of Medicine of University of Geneva
Dinu Lipatti Foundation
China Scholarship Council
Syöpäsäätiö
Sir Jules Thorn Charitable Overseas Trust Reg
Geneva Cancer Foundation
Sigrid Juséliuksen Säätiö
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	310030-185261
Strategic Research Council at the Research Council of Finland	323021
National Institutes of Health	GM119560
American Cancer Society	RSG-15-167-01-DMC

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SDG 3 – Hyvä terveys ja hyvinvointi

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10.1016/j.isci.2024.110129Lisenssi: CC BY

1-s2.0-S2589004224013543-mainFinal published version, 12,7 MBLisenssi: CC BY

https://urn.fi/URN:NBN:fi:tuni-202407127611Lisenssi: CC BY

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title = "Acetyl-NPKY of integrin-β1 binds KINDLIN2 to control endothelial cell proliferation and junctional integrity",

abstract = "Integrin-dependent crosstalk between cell-matrix adhesions and cell-cell junctions is critical for controlling endothelial permeability and proliferation in cancer and inflammatory diseases but remains poorly understood. Here, we investigated how acetylation of the distal NPKY-motif of Integrin-β1 influences endothelial cell physiology and barrier function. Expression of an acetylation-mimetic β1-K794Q-GFP mutant led to the accumulation of immature cell-matrix adhesions accompanied by a transcriptomic reprograming of endothelial cells, involving genes associated with cell adhesion, proliferation, polarity, and barrier function. β1-K794Q-GFP induced constitutive MAPK signaling, junctional impairment, proliferation, and reduced contact inhibition at confluence. Structural analysis of Integrin-β1 interaction with KINDLIN2, biochemical pulldown assay, and binding energy determination by using molecular dynamics simulation showed that acetylation of K794 and the K794Q-mutant increased KINDLIN2 binding affinity to the Integrin-β1. Thus, enhanced recruitment of KINDLIN2 to Lysine-acetylated Integrin-β1 and resulting modulation of barrier function, offers new therapeutic possibilities for controlling vascular permeability and disease conditions.",

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author = "Adama Sidib{\'e} and Mykuliak, \{Vasyl V.\} and Pingfeng Zhang and Hyt{\"o}nen, \{Vesa P.\} and Jinhua Wu and Bernhard Wehrle-Haller",

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doi = "10.1016/j.isci.2024.110129",

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T1 - Acetyl-NPKY of integrin-β1 binds KINDLIN2 to control endothelial cell proliferation and junctional integrity

AU - Sidibé, Adama

AU - Mykuliak, Vasyl V.

AU - Zhang, Pingfeng

AU - Hytönen, Vesa P.

AU - Wu, Jinhua

AU - Wehrle-Haller, Bernhard

PY - 2024/6/21

Y1 - 2024/6/21

N2 - Integrin-dependent crosstalk between cell-matrix adhesions and cell-cell junctions is critical for controlling endothelial permeability and proliferation in cancer and inflammatory diseases but remains poorly understood. Here, we investigated how acetylation of the distal NPKY-motif of Integrin-β1 influences endothelial cell physiology and barrier function. Expression of an acetylation-mimetic β1-K794Q-GFP mutant led to the accumulation of immature cell-matrix adhesions accompanied by a transcriptomic reprograming of endothelial cells, involving genes associated with cell adhesion, proliferation, polarity, and barrier function. β1-K794Q-GFP induced constitutive MAPK signaling, junctional impairment, proliferation, and reduced contact inhibition at confluence. Structural analysis of Integrin-β1 interaction with KINDLIN2, biochemical pulldown assay, and binding energy determination by using molecular dynamics simulation showed that acetylation of K794 and the K794Q-mutant increased KINDLIN2 binding affinity to the Integrin-β1. Thus, enhanced recruitment of KINDLIN2 to Lysine-acetylated Integrin-β1 and resulting modulation of barrier function, offers new therapeutic possibilities for controlling vascular permeability and disease conditions.

AB - Integrin-dependent crosstalk between cell-matrix adhesions and cell-cell junctions is critical for controlling endothelial permeability and proliferation in cancer and inflammatory diseases but remains poorly understood. Here, we investigated how acetylation of the distal NPKY-motif of Integrin-β1 influences endothelial cell physiology and barrier function. Expression of an acetylation-mimetic β1-K794Q-GFP mutant led to the accumulation of immature cell-matrix adhesions accompanied by a transcriptomic reprograming of endothelial cells, involving genes associated with cell adhesion, proliferation, polarity, and barrier function. β1-K794Q-GFP induced constitutive MAPK signaling, junctional impairment, proliferation, and reduced contact inhibition at confluence. Structural analysis of Integrin-β1 interaction with KINDLIN2, biochemical pulldown assay, and binding energy determination by using molecular dynamics simulation showed that acetylation of K794 and the K794Q-mutant increased KINDLIN2 binding affinity to the Integrin-β1. Thus, enhanced recruitment of KINDLIN2 to Lysine-acetylated Integrin-β1 and resulting modulation of barrier function, offers new therapeutic possibilities for controlling vascular permeability and disease conditions.

KW - Cell

KW - Cell biology

KW - Structural biology

U2 - 10.1016/j.isci.2024.110129

DO - 10.1016/j.isci.2024.110129

M3 - Article

AN - SCOPUS:85195281642

SN - 2589-0042

VL - 27

JO - iScience

JF - iScience

IS - 6

M1 - 110129

ER -

Acetyl-NPKY of integrin-β1 binds KINDLIN2 to control endothelial cell proliferation and junctional integrity

Abstrakti

Rahoitus

YK:n kestävän kehityksen tavoitteet

Julkaisufoorumi-taso

!!ASJC Scopus subject areas

Pääsy asiakirjaan

Sormenjälki

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