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 language | English |
|---|---|
| Article number | e202310030 |
| Number of pages | 22 |
| Journal | Journal of Cell Biology |
| Volume | 223 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 2 Sept 2024 |
| MoE publication type | A1 Journal article-refereed |
Funding
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).
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