Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 28, Pages 9691-9711Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.013973
Keywords
innate immunity; retinoic acid-inducible gene I protein (RIG-I); tripartite motif-containing 25 (TRIM25); melanoma differentiation?associated protein 5 (MDA5); severe fever with thrombocytopenia syndrome virus (SFTSV); nonstructural protein (NSs); inclusion body (IB); immune evasion; virus-host interaction; virulence factor; virology; infectious disease; viral immunology
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Funding
- National Natural Science Foundation of China [31700146, 31870162, 31621061, 31600144]
- National Key Research and Development Program of China [2018YFA0507202]
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The RIG-I?like receptors (RLRs) retinoic acid?inducible gene I protein (RIG-I) and melanoma differentiation?associated protein 5 (MDA5) are cytosolic pattern recognition receptors that recognize specific viral RNA products and initiate antiviral innate immunity. Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic member of theBunyavirales. RIG-I, but not MDA5, has been suggested to sense some bunyavirus infections; however, the roles of RLRs in anti-SFTSV immune responses remain unclear. Here, we show that SFTSV infection induces an antiviral response accompanied by significant induction of antiviral and inflammatory cytokines and that RIG-I plays a main role in this induction by recognizing viral 5?-triphosphorylated RNAs and by signaling via the adaptor mitochondrial antiviral signaling protein. Moreover, MDA5 may also sense SFTSV infection and contribute to IFN induction, but to a lesser extent. We further demonstrate that the RLR-mediated anti-SFTSV signaling can be antagonized by SFTSV nonstructural protein (NSs) at the level of RIG-I activation. Protein interaction and MS-based analyses revealed that NSs interacts with the host protein tripartite motif?containing 25 (TRIM25), a critical RIG-I?activating ubiquitin E3 ligase, but not with RIG-I or Riplet, another E3 ligase required for RIG-I ubiquitination. NSs specifically trapped TRIM25 into viral inclusion bodies and inhibited TRIM25-mediated RIG-I-Lys-63?linked ubiquitination/activation, contributing to suppression of RLR-mediated antiviral signaling at its initial stage. These results provide insights into immune responses to SFTSV infection and clarify a mechanism of the viral immune evasion, which may help inform the development of antiviral therapeutics.
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