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TLNRD1 is a CCM complex component and regulates endothelial barrier integrity

Ball, Neil J., Ghimire, Sujan, Follain, Gautier, Pajari, Ada O, Wurzinger, Diana, Vaitkevičiūtė, Monika, Cowell, Alana R, Berki, Bence, Ivaska, Johanna, Paatero, Ilkka, and others. (2024) TLNRD1 is a CCM complex component and regulates endothelial barrier integrity. Journal of Cell Biology, 223 (9). Article Number e202310030. ISSN 0021-9525. (doi:10.1083/jcb.202310030) (KAR id:106572)

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.

Item Type: Article
DOI/Identification number: 10.1083/jcb.202310030
Uncontrolled keywords: Talin, actin, CCM
Subjects: Q Science > QH Natural history > QH581.2 Cell Biology
Divisions: Divisions > Division of Natural Sciences > Biosciences
Funders: Cancer Research UK (https://ror.org/054225q67)
Depositing User: Ben Goult
Date Deposited: 17 Jul 2024 07:49 UTC
Last Modified: 18 Jul 2024 10:03 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/106572 (The current URI for this page, for reference purposes)

University of Kent Author Information

Ball, Neil J..

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CReDIT Contributor Roles:

Goult, Benjamin T.

Creator's ORCID: https://orcid.org/0000-0002-3438-2807
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