Biochemical and Functional Characterization of the Mitochondrial Immune Signaling Protein Complex Public Deposited

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  • June 7, 2019
Creator
  • Lei, Yu
    • Affiliation: School of Dentistry, Oral and Craniofacial Biomedicine PhD Program
Abstract
  • The mitochondrion has emerged as a crucial organelle where key anti-viral responses including apoptosis, type 1 interferon (IFN-I) production and autophagy are regulated. A prime example is the intersection of the mitochondrial protein MAVS with the RLR (RIG-I-like receptors) to induce IFN-I. Here we show that MAVS is a pro-apoptotic protein independent of its function in initiating IFN-I production. Viral proteins such as NS3/4A encoded by HCV and NSP15 encoded by SARS-CoV inhibit this response. MAVS-mediated IFN-I is tightly regulated by an NLR (nucleotide-binding domain, leucine-rich repeats containing) protein NLRX1. More in-depth analysis utilizing cells from gene-deletion mice indicates that NLRX1 not only attenuates IFN-I production, it additionally promotes autophagy during viral infection. This dual regulatory function of NLRX1 parallels the previously described functions of Atg5-Atg12, although NLRX1 does not associate with Atg5-Atg12. High throughput quantitative mass spectrometry and biochemical analysis revealed a novel NLRX1-interacting partner, mitochondrial Tu translation elongation factor (TUFM/P43/EF-Tu/COXPD4/ EF-TuMT), which does interact with Atg5-Atg12. Similar to NLRX1, TUFM potently inhibits RLR signaling and promotes autophagy during a viral infection. This thesis demonstrates the dual roles of MAVS in controlling both IFN-I and apoptosis, and establishes the first link between an NLR protein and a viral-induced autophagic machinery via TUFM.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Oral Biology, School of Dentistry.
Advisor
  • Ting, Jenny P.-Y.
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