TLNRD1 is a CCM complex component and regulates endothelial barrier integrity
Year: 2024
Type: article
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.
Source: The Journal of Cell Biology
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Helsingin Yliopisto, UK Research and Innovation, Finnish Cancer Institute, Cancer Research UK, Academy of Finland, Jane ja Aatos Erkon Säätiö, Turun Yliopisto, Sigrid Juséliuksen Säätiö, Syöpäjärjestöt, Stiftelsen för Åbo Akademi, Åbo Akademi, Biocenter Finland, Directorate for Biological Sciences, Helsinki Institute of Life Science, Helsingin Yliopisto, Biotechnology and Biological Sciences Research Council
Awards: G1166116973, G1849284932, G2683027318, InFLAMES: Innovation Ecosystem based on the Immune System, Deciphering the mechanisms of pancreatic cancer metastasis (PanCanMet), InFLAMES: Innovation Ecosystem based on the Immune System, G4616707129, InFLAMES: Innovation Ecosystem based on the Immune System, G7380206894, Harnessing protein unfolding and aggregation in mechanotransduction, G7589036865, Filopodia-mediated communication in cancer progression (FILOCOM), InFLAMES: Innovation Ecosystem based on the Immune System, Biological Barrier Mechanics and Disease: From molecular-scale to tissue-level understanding of signal integration and forces (BarrierForce), G8697803143
OpenAlex ID: W4400675925