TLNRD1 is a CCM complex component and regulates endothelial barrier integrity

Neil J Ball; Sujan Ghimire; Gautier Follain; Ada O Pajari; Diana Wurzinger; Monika Vaitkevičiūtė; Alana R Cowell; Bence Berki; Johanna Ivaska; Ilkka Paatero; Benjamin T Goult; Guillaume Jacquemet

doi:10.1083/jcb.202310030

TLNRD1 is a CCM complex component and regulates endothelial barrier integrity

Neil J Ball
, Sujan Ghimire
, Gautier Follain
, Ada O Pajari
, Diana Wurzinger
, Monika Vaitkevičiūtė
, Alana R Cowell
, Bence Berki
, Johanna Ivaska
, Ilkka Paatero
, Benjamin T Goult
, Guillaume Jacquemet

Tutkimustuotos: Lehtiartikkeli › Artikkeli › Tieteellinen › vertaisarvioitu

4 Sitaatiot (Scopus)

122 Lataukset (Pure)

Abstrakti

We previously identified talin rod domain-containing protein 1 (TLNRD1) as a potent actin-bundling protein in vitro. Here, we report that TLNRD1 is expressed in the vasculature in vivo. Its depletion leads to vascular abnormalities in vivo and modulation of endothelial cell monolayer integrity in vitro. We demonstrate that TLNRD1 is a component of the cerebral cavernous malformations (CCM) complex through its direct interaction with CCM2, which is mediated by a hydrophobic C-terminal helix in CCM2 that attaches to a hydrophobic groove on the four-helix domain of TLNRD1. Disruption of this binding interface leads to CCM2 and TLNRD1 accumulation in the nucleus and actin fibers. Our findings indicate that CCM2 controls TLNRD1 localization to the cytoplasm and inhibits its actin-bundling activity and that the CCM2-TLNRD1 interaction impacts endothelial actin stress fiber and focal adhesion formation. Based on these results, we propose a new pathway by which the CCM complex modulates the actin cytoskeleton and vascular integrity.

Alkuperäiskieli	Englanti
Artikkeli	e202310030
Sivumäärä	22
Julkaisu	Journal of Cell Biology
Vuosikerta	223
Numero	9
DOI - pysyväislinkit	https://doi.org/10.1083/jcb.202310030
Tila	Julkaistu - 2 syysk. 2024
OKM-julkaisutyyppi	A1 Julkaistu artikkeli, soviteltu

Rahoitus

The Cell Imaging and Cytometry Core facility, the Zebrafish Core (both at Turku Bioscience, University of Turku, \u00C5bo Akademi University, and supported by Biocenter Finland), and Turku Bioimaging and the Genome Biology Unit (Research Programs Unit, HiLIFE Helsinki Institute of Life Science, Faculty of Medicine, University of Helsinki, Biocenter Finland) are acknowledged for services, instrumentation, and expertise. Mass spectrometry was performed at the Turku Proteomics Facility, University of Turku and \u00C5bo Akademi University. The facility is supported by Biocenter Finland. This study was supported by the Research Council of Finland (338537 to G. Jacquemet; 325464 to J. Ivaska; and 332402 to G. Follain), the Sigrid Juselius Foundation (to G. Jacquemet and to J. Ivaska), the Cancer Society of Finland (Sy\u00F6p\u00E4j\u00E4rjest\u00F6t; to G. Jacquemet and to J. Ivaska), and the Solutions for Health strategic funding to \u00C5bo Akademi University (to G. Jacquemet). This research was supported by the InFLAMES Flagship Programme of the Academy of Finland (decision numbers: 337530, 337531, 357910, and 357911). This work was also supported by the Finnish Cancer Institute (K. Albin Johansson Professorship, J. Ivaska), the Centre of Excellence program (# 346131, J. Ivaska), and the Jane and Aatos Erkko Foundation (J. Ivaska). B.T. Goult was supported by the Biotechnology and Biological Sciences Research Council grant (BB/S007245/1) and the Cancer Research UK Program Grant (CRUK-A21671). The open access publication fees were funded by the G\u00F6sta Branders research fund, \u00C5bo Akademi Research Foundation (G\u00F6sta Branders forskningsfond, Stiftelsen f\u00F6r \u00C5bo Akademi).

Pääsy asiakirjaan

10.1083/jcb.202310030

jcb_202310030Lopullinen julkaistu versio, 9,41 MBLisenssi: CC BY

https://urn.fi/URN:NBN:fi-fe2024091370950

Viittausmuodot

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title = "TLNRD1 is a CCM complex component and regulates endothelial barrier integrity",

abstract = "We previously identified talin rod domain-containing protein 1 (TLNRD1) as a potent actin-bundling protein in vitro. Here, we report that TLNRD1 is expressed in the vasculature in vivo. Its depletion leads to vascular abnormalities in vivo and modulation of endothelial cell monolayer integrity in vitro. We demonstrate that TLNRD1 is a component of the cerebral cavernous malformations (CCM) complex through its direct interaction with CCM2, which is mediated by a hydrophobic C-terminal helix in CCM2 that attaches to a hydrophobic groove on the four-helix domain of TLNRD1. Disruption of this binding interface leads to CCM2 and TLNRD1 accumulation in the nucleus and actin fibers. Our findings indicate that CCM2 controls TLNRD1 localization to the cytoplasm and inhibits its actin-bundling activity and that the CCM2-TLNRD1 interaction impacts endothelial actin stress fiber and focal adhesion formation. Based on these results, we propose a new pathway by which the CCM complex modulates the actin cytoskeleton and vascular integrity.",

keywords = "Humans, Animals, Hemangioma, Cavernous, Central Nervous System/metabolism, Human Umbilical Vein Endothelial Cells/metabolism, Endothelial Cells/metabolism, Focal Adhesions/metabolism, Carrier Proteins/metabolism, Stress Fibers/metabolism, Actins/metabolism, Actin Cytoskeleton/metabolism, Protein Binding, Mice, Cell Nucleus/metabolism, Talin",

author = "Ball, \{Neil J\} and Sujan Ghimire and Gautier Follain and Pajari, \{Ada O\} and Diana Wurzinger and Monika Vaitkevi{\v c}iūtė and Cowell, \{Alana R\} and Bence Berki and Johanna Ivaska and Ilkka Paatero and Goult, \{Benjamin T\} and Guillaume Jacquemet",

note = "{\textcopyright} 2024 Ball et al.",

year = "2024",

month = sep,

day = "2",

doi = "10.1083/jcb.202310030",

language = "English",

volume = "223",

journal = "Journal of Cell Biology",

issn = "0021-9525",

publisher = "Rockefeller university press",

number = "9",

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TY - JOUR

T1 - TLNRD1 is a CCM complex component and regulates endothelial barrier integrity

AU - Ball, Neil J

AU - Ghimire, Sujan

AU - Follain, Gautier

AU - Pajari, Ada O

AU - Wurzinger, Diana

AU - Vaitkevičiūtė, Monika

AU - Cowell, Alana R

AU - Berki, Bence

AU - Ivaska, Johanna

AU - Paatero, Ilkka

AU - Goult, Benjamin T

AU - Jacquemet, Guillaume

PY - 2024/9/2

Y1 - 2024/9/2

N2 - We previously identified talin rod domain-containing protein 1 (TLNRD1) as a potent actin-bundling protein in vitro. Here, we report that TLNRD1 is expressed in the vasculature in vivo. Its depletion leads to vascular abnormalities in vivo and modulation of endothelial cell monolayer integrity in vitro. We demonstrate that TLNRD1 is a component of the cerebral cavernous malformations (CCM) complex through its direct interaction with CCM2, which is mediated by a hydrophobic C-terminal helix in CCM2 that attaches to a hydrophobic groove on the four-helix domain of TLNRD1. Disruption of this binding interface leads to CCM2 and TLNRD1 accumulation in the nucleus and actin fibers. Our findings indicate that CCM2 controls TLNRD1 localization to the cytoplasm and inhibits its actin-bundling activity and that the CCM2-TLNRD1 interaction impacts endothelial actin stress fiber and focal adhesion formation. Based on these results, we propose a new pathway by which the CCM complex modulates the actin cytoskeleton and vascular integrity.

AB - We previously identified talin rod domain-containing protein 1 (TLNRD1) as a potent actin-bundling protein in vitro. Here, we report that TLNRD1 is expressed in the vasculature in vivo. Its depletion leads to vascular abnormalities in vivo and modulation of endothelial cell monolayer integrity in vitro. We demonstrate that TLNRD1 is a component of the cerebral cavernous malformations (CCM) complex through its direct interaction with CCM2, which is mediated by a hydrophobic C-terminal helix in CCM2 that attaches to a hydrophobic groove on the four-helix domain of TLNRD1. Disruption of this binding interface leads to CCM2 and TLNRD1 accumulation in the nucleus and actin fibers. Our findings indicate that CCM2 controls TLNRD1 localization to the cytoplasm and inhibits its actin-bundling activity and that the CCM2-TLNRD1 interaction impacts endothelial actin stress fiber and focal adhesion formation. Based on these results, we propose a new pathway by which the CCM complex modulates the actin cytoskeleton and vascular integrity.

KW - Humans

KW - Animals

KW - Hemangioma, Cavernous, Central Nervous System/metabolism

KW - Human Umbilical Vein Endothelial Cells/metabolism

KW - Endothelial Cells/metabolism

KW - Focal Adhesions/metabolism

KW - Carrier Proteins/metabolism

KW - Stress Fibers/metabolism

KW - Actins/metabolism

KW - Actin Cytoskeleton/metabolism

KW - Protein Binding

KW - Mice

KW - Cell Nucleus/metabolism

KW - Talin

U2 - 10.1083/jcb.202310030

DO - 10.1083/jcb.202310030

M3 - Article

C2 - 39013281

SN - 0021-9525

VL - 223

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 9

M1 - e202310030

ER -

TLNRD1 is a CCM complex component and regulates endothelial barrier integrity

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