Xu, Z.; Lu, J.; Gao, S.; Rui, Y.-N. THSD1 Suppresses Autophagy-Mediated Focal Adhesion Turnover by Modulating the FAK-Beclin 1 Pathway. Int. J. Mol. Sci.2024, 25, 2139.
Xu, Z.; Lu, J.; Gao, S.; Rui, Y.-N. THSD1 Suppresses Autophagy-Mediated Focal Adhesion Turnover by Modulating the FAK-Beclin 1 Pathway. Int. J. Mol. Sci. 2024, 25, 2139.
Xu, Z.; Lu, J.; Gao, S.; Rui, Y.-N. THSD1 Suppresses Autophagy-Mediated Focal Adhesion Turnover by Modulating the FAK-Beclin 1 Pathway. Int. J. Mol. Sci.2024, 25, 2139.
Xu, Z.; Lu, J.; Gao, S.; Rui, Y.-N. THSD1 Suppresses Autophagy-Mediated Focal Adhesion Turnover by Modulating the FAK-Beclin 1 Pathway. Int. J. Mol. Sci. 2024, 25, 2139.
Abstract
Focal adhesions (FAs) play a crucial role in cell spreading and adhesion, and their autophagic degradation is an emerging area of interest. Our 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, in an autophagy-dependent manner. Intriguingly, THSD1-mediated autophagy activation operates 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. Interestingly, THSD1 negatively regulates Beclin 1, a central autophagy regulator, at FAs through interactions with focal adhesion kinase (FAK). The loss of THSD1 diminishes FAK activity, consequently relieving 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.
Biology and Life Sciences, Biochemistry and Molecular Biology
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