Understanding host-viral interaction is an essential step in developing safe and effective antimicrobials against biodefense agents and emerging pathogens. Early detection of invading viruses by the host depends on a limited number of specific intracellular receptors that detect viral patterns and activate signal transduction cascades, thereby triggering interferon (IFN)-mediated anti-viral defense mechanisms. Retinoic acid-inducible gene I (RIG-I) has emerged as a key cytosolic viral RNA receptor for sensing emerging viruses, including the influenza virus and hepatitis virus C (HCV). In addition, members of the tripartite motif (TRIM) protein family, containing a RING-finger domain, B box/coiled-coil domain (B Box/CCD), and a SPRY domain, play a major role in the inhibition of the lifecycles of viruses. Furthermore, the interconnection between the RIG-I and TRIM family is required to initiate the induction of the protective IFN-mediated host anti-viral innate immunity. Our collaborative works have demonstrated that the RIG-Imediated IFN pathway requires multiple step processes: upon viral infection, the C-terminal "regulatory" domain (RD) of RIG-I recognizes viral RNA in a 5'-triphosphate-dependent manner, leading to RIG-I dimerization and ATPase activity. Subsequently, RIG-I undergo a robust ubiquitination induced by the TRIM25 E3 ligase, enabling RIG-I to interact with the downstream CARD-containing mitochondrial anti-viral signaling (MAVS) protein and thereby inducing antiviral signal transduction to limit viral replication and transmission. The goal of this study focuses on better understanding the regulation of RIG-I and TRIM25 pathways: how posttranslational modifications affect RIG-I and TRIM25 signaling activity (Aim 1), what the modes of feedback regulation for the RIG-I and TRIM25 pathways are (Aim 2), and finally, what roles RIG-I and TRIM25 mediated immune surveillance have against viruses (Aim 3). Thus, the proposed study will attempt to delineate the molecular mechanisms underlying the host-viral interaction at a basic scientific level and will also provide the foundations for developing novel diagnostic and therapeutic strategies for emerging virus-associated disorders at the public health level.

Public Health Relevance

Understanding of host-viral interaction is an essential step to develop safe and effective antimicrobials against biodefense agents and emerging pathogens. RIG-I and TRIM protein family play major roles in the inhibition of lifecycles of viruses. The proposed study is targeted to delineate the molecular mechanism underlying the host-viral interaction, with a specific focus on the RIG-I- and TRIM25-mediated IFN response.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BDP-I)
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University of Southern California
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Rajsbaum, Ricardo; Garcia-Sastre, Adolfo; Versteeg, Gijs A (2014) TRIMmunity: the roles of the TRIM E3-ubiquitin ligase family in innate antiviral immunity. J Mol Biol 426:1265-84
Shi, Mude; Cho, Hyelim; Inn, Kyung-Soo et al. (2014) Negative regulation of NF-?B activity by brain-specific TRIpartite Motif protein 9. Nat Commun 5:4820
Peterson, Joseph R; Labhsetwar, Piyush; Ellermeier, Jeremy R et al. (2014) Towards a computational model of a methane producing archaeum. Archaea 2014:898453
Runge, Simon; Sparrer, Konstantin M J; Lässig, Charlotte et al. (2014) In vivo ligands of MDA5 and RIG-I in measles virus-infected cells. PLoS Pathog 10:e1004081
Deimling, Tobias; Cui, Sheng; Lammens, Katja et al. (2014) Crystal and solution structure of the human RIG-I SF2 domain. Acta Crystallogr F Struct Biol Commun 70:1027-31
Santiago, Felix W; Covaleda, Lina M; Sanchez-Aparicio, Maria T et al. (2014) Hijacking of RIG-I signaling proteins into virus-induced cytoplasmic structures correlates with the inhibition of type I interferon responses. J Virol 88:4572-85
Rajsbaum, Ricardo; Versteeg, Gijs A; Schmid, Sonja et al. (2014) Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKK? kinase-mediated antiviral response. Immunity 40:880-95
Ayllon, Juan; Domingues, Patricia; Rajsbaum, Ricardo et al. (2014) A single amino acid substitution in the novel H7N9 influenza A virus NS1 protein increases CPSF30 binding and virulence. J Virol 88:12146-51
Roth, Susanne; Rottach, Andrea; Lotz-Havla, Amelie S et al. (2014) Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1? production. Nat Immunol 15:538-45
Pulloor, Niyas Kudukkil; Nair, Sajith; McCaffrey, Kathleen et al. (2014) Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in Type-I interferon response. PLoS Pathog 10:e1003981

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