Faculty, Staff and Student Publications
Publication Date
2-10-2024
Journal
International Journal of Molecular Sciences
Abstract
Focal adhesions (FAs) play a crucial role in cell spreading and adhesion, and their autophagic degradation is an emerging area of interest. This study investigates the role of Thrombospondin Type 1 Domain-Containing Protein 1 (THSD1) in regulating autophagy and FA stability in brain endothelial cells, shedding light on its potential implications for cerebrovascular diseases. Our research reveals a physical interaction between THSD1 and FAs. Depletion of THSD1 significantly reduces FA numbers, impairing cell spreading and adhesion. The loss of THSD1 also induces autophagy independently of changes in mTOR and AMPK activation, implying that THSD1 primarily governs FA dynamics rather than serving as a global regulator of nutrient and energy status. Mechanistically, THSD1 negatively regulates Beclin 1, a central autophagy regulator, at FAs through interactions with focal adhesion kinase (FAK). THSD1 inactivation diminishes FAK activity and relieves its inhibitory phosphorylation on Beclin 1. This, in turn, promotes the complex formation between Beclin 1 and ATG14, a critical event for the activation of the autophagy cascade. In summary, our findings identify THSD1 as a novel regulator of autophagy that degrades FAs in brain endothelial cells. This underscores the distinctive nature of THSD1-mediated, cargo-directed autophagy and its potential relevance to vascular diseases due to the loss of endothelial FAs. Investigating the underlying mechanisms of THSD1-mediated pathways holds promise for discovering novel therapeutic targets in vascular diseases.
Keywords
Humans, Autophagy, Beclin-1, Endothelial Cells, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesions, Phosphorylation, Vascular Diseases, Thrombospondins, THSD1, autophagy, focal adhesions, Beclin 1, endothelial cells
DOI
10.3390/ijms25042139
PMID
38396816
PMCID
PMC10889294
PubMedCentral® Posted Date
2-10-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes