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

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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.

Original languageEnglish
Article numbere202310030
Number of pages22
JournalJournal of Cell Biology
Volume223
Issue number9
DOIs
Publication statusPublished - 2 Sept 2024
MoE publication typeA1 Journal article-refereed

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

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