PDF(Pubmed)
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.
摘要：
局灶性粘连（FAs）在细胞扩散和粘附中起着至关重要的作用，它们的自噬降解是一个新兴的兴趣领域。本研究探讨了血小板反应蛋白1型结构域蛋白1（THSD1）在调节脑内皮细胞自噬和FA稳定性中的作用。阐明其对脑血管疾病的潜在影响。我们的研究揭示了THSD1和FA之间的物理相互作用。THSD1的耗尽显著减少了FA数量，损害细胞扩散和粘附。THSD1的缺失也诱导自噬，而不依赖于mTOR和AMPK激活的变化。这意味着THSD1主要控制FA动力学，而不是作为营养和能量状态的全球调节器。机械上,THSD1负调节Beclin1，中枢自噬调节因子，通过与粘着斑激酶（FAK）的相互作用在FAs。THSD1失活会降低FAK活性并减轻其对Beclin1的抑制磷酸化。这个,反过来,促进Beclin1和ATG14之间的复合物形成，这是激活自噬级联的关键事件。总之,我们的研究发现THSD1是一种新型的自噬调节因子,可降解脑内皮细胞中的FAs.这强调了THSD1介导的独特性质，货物导向的自噬及其与内皮FAs丢失导致的血管疾病的潜在相关性。研究THSD1介导途径的潜在机制有望在血管疾病中发现新的治疗靶标。
