A RIG-I–like receptor directs antiviral responses to a bunyavirus and is antagonized by virus-induced blockade of TRIM25-mediated ubiquitination

Abstract

<jats:p>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 the <jats:italic>Bunyavirales</jats:italic>. 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.</jats:p>

Host restriction of emerging high-pathogenic bunyaviruses via MOV10 by targeting viral nucleoprotein and blocking ribonucleoprotein assembly

“…The genomic accession numbers are as follows: JQ341190.1 (SFTSV S segment), JQ341189.1 (SFTSV M segment) and JQ341188.1 (SFTSV L segment); NC_043610.1 (GTV S segment), NC_043609.1 (GTV M segment) and NC_043611.1 (GTV L segment); NC_024496.1 (HRTV S segment), NC_024494.1 (HRTV M segment), and NC_024495.1 (HRTV L segment). Bunyavirus titers were determined in Vero cells by 50% tissue culture infectious dose (TCID50) method [ 15 , 17 , 58 ]. Sendai virus (SeV) was propagated in 10-day-old embryonated eggs and titrated by hemagglutination assay as previously described [ 18 ].…”

A Look into Bunyavirales Genomes: Functions of Non-Structural (NS) Proteins

“…Lastly, SFTSV NSs functions to increase virulence independent of the IFN systems. This includes upregulating the p62-Keap1-Nrf2 antioxidant pathway [ 144 ], inducing interleukin 10 (IL-10) expression involved in host immune response [ 145 ], suppressing NF-κB promoter activities to avoid innate immunity signaling [ 146 ], interacting with TRIM25 to mediate antiviral signaling [ 147 ], and promoting cell cycle arrest [ 148 ]. Further, although SFTSV NSs is dispensable for viral replication [ 128 ], it can form viroplasm-like structures (VLSs) in infected cells and these serve as sites of viral dsRNA localization, indicating a potential novel role of NSs in enhancing SFTSV replication [ 149 ].…”

RCO-3 and COL-26 form an external-to-internal module that regulates the dual-affinity glucose transport system in Neurospora crassa

“…Western blotting was performed as previously described [ 103 ]. Anti-GFP or anti-actin rabbit antibody and anti-rabbit IgG horseradish peroxidase-conjugated antibody at a dilution of 1:3000 were used as the primary and secondary antibodies (Abmart, Shanghai, China), respectively.…”