Structural mechanism of integrin-mediated TGF-b activation

摘要/摘要：TGF-驱动纤维炎症过程，导致肺和气道纤维化。这个

Summary/Abstract: TGF- drives the fibroinflammatory processes that leads to lung and airway fibrosis. The long-term goal of this project is to acquire a deep understanding of the regulation of TGF- activity to develop new strategies and treatments for fibrosing lung disease. There are few effective therapies to treat chronic fibrosing and inflammatory diseases of the lung. The cytokine TGF- is a central mediator of fibrosis and pathologic inflammation and is a potential therapeutic target in fibrosing lung disease. However, the practical utility of targeting TGF- itself or its receptors is limited by risk of toxicities seen in rodents, primates and humans. More specific methods to target the fibroinflammatory effects of TGF- are highly desirable. A promising method to more specifically target local effects of TGF- is to target its “activation” since it is always produced in a latent form (L-TGF-) that must be activated in order to function. Another feature of L-TGF- that could facilitate more specific targeting is that it is covalently bound to specific cell surfaces by GARP. L-TGF- binding to the integrin v8 is essential for TGF- activation in vivo. For the v8 activation mechanism, as well as all others, it has long been assumed that TGF- must be released from LAP so that free TGF- can diffuse and bind its receptors on target cells. Based on recent structural data obtained using single particle electron cryomicroscopy (cryo-EM), we have recently proposed a new model whereby v8 can bind to L- TGF- on cells presenting the L-TGF-/GARP complex and induce signaling without release and diffusion of TGF-. Here in three aims, we address three critical questions concerning this new model of L-TGF- activation. (1) Which flexible domains of L-TGF- of the v8/L-TGF-/GARP ternary complex shield TGF- from its receptors? (2) Is flexibility of L-TGF- induced by binding to v8 necessary to mediate TGF- activation? (3) Do TGF- receptors (TGF-Rs) bind to TGF- within the v8/L-TGF-/GARP complex? To answer these questions, we will use cryo-EM to determine the structure of the v8/L-TGF-/GARP complex to determine how flexibility of L-TGF- contributes to TGF- activation, and finally we will capture the multimeric complex of TGF-Rs with v8/LTGF-/GARP. These studies will improve mechanistic understanding of TGF- activation and therapeutic targeting strategies to inhibit it.