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      Beclin1 Haploinsufficiency accentuates second-hand smoke exposure -induced myocardial Remodeling and contractile dysfunction through a STING-mediated mechanism

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          Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.

          The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.
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            Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation.

            During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.
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              Autophagy Induction via STING Trafficking Is a Primordial Function of the cGAS Pathway

              Cyclic GMP-AMP (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self-DNA in the cytoplasm 1 . Upon binding DNA, cGAS produces cGAMP that binds to and activates the adaptor protein STING, which then activates the kinases IKK and TBK1 to induce interferons and other cytokines 2–6 . Here, we report that STING also activates autophagy through a mechanism independent of TBK1 activation and interferon induction. Upon binding cGAMP, STING translocates to the ER-Golgi intermediate compartment (ERGIC) and the Golgi in a process dependent on the COP-II complex and ARF GTPases. STING-containing ERGIC serves as a membrane source for LC3 lipidation, a key step in autophagosome biogenesis. cGAMP induced LC3 lipidation through a pathway dependent on WIPI2 and ATG5 but independent of the ULK and VPS34/BECLIN kinase complexes. Furthermore, we show that cGAMP-induced autophagy is important for the clearance of DNA and viruses in the cytosol. Interestingly, STING from the sea anemone Nematostella vectensis induces autophagy but not interferons in response to stimulation by cGAMP, suggesting that induction of autophagy is a primordial function of the cGAS-STING pathway.
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                Author and article information

                Journal
                Journal of Molecular and Cellular Cardiology
                Journal of Molecular and Cellular Cardiology
                Elsevier BV
                00222828
                November 2020
                November 2020
                : 148
                : 78-88
                Article
                10.1016/j.yjmcc.2020.08.016
                32891637
                84075489-6377-4d47-8d52-e3fb163234de
                © 2020

                https://www.elsevier.com/tdm/userlicense/1.0/

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