A1 Refereed original research article in a scientific journal
TLNRD1 is a CCM complex component and regulates endothelial barrier integrity
Authors: Ball, Neil J.; Ghimire, Sujan; Follain, Gautier; Pajari, Ada O.; Wurzinger, Diana; Vaitkevičiūtė, Monika; Cowell, Alana R.; Berki, Bence; Ivaska, Johanna; Paatero, Ilkka; Goult, Benjamin T.; Jacquemet, Guillaume
Publisher: Rockefeller University Press
Publication year: 2024
Journal: Journal of Cell Biology
Journal name in source: The Journal of cell biology
Journal acronym: J Cell Biol
Article number: e202310030
Volume: 223
Issue: 9
ISSN: 0021-9525
eISSN: 1540-8140
DOI: https://doi.org/10.1083/jcb.202310030
Web address : https://rupress.org/jcb/article/223/9/e202310030/276861/TLNRD1-is-a-CCM-complex-component-and-regulates
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/457256769
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.
Downloadable publication This is an electronic reprint of the original article. |  |
Funding information in the publication:
Research funded by Research Council of Finland (338537,325464,332402) | Academy of Finland (337530,337531,357910,357911) | Centre of Excellence (# 346131) | Biotechnology and Biological Sciences Research Council (BB/S007245/1) | Cancer Research UK (CRUK-A21671)
