Abstract
Respiratory syncytial virus (RSV) causes severe acute lower respiratory tract disease. Retinoic acid-inducible gene-I (RIG-I) serves as an innate immune sensor and triggers antiviral responses upon recognizing viral infections including RSV. Since tripartite motif-containing protein 25 (TRIM25)-mediated K63-polyubiquitination is crucial for RIG-I activation, several viruses target initial RIG-I activation through ubiquitination. RSV NS1 and NS2 have been shown to interfere with RIG-I-mediated antiviral signaling. In this study, we explored the possibility that NS1 suppresses RIG-I-mediated antiviral signaling by targeting TRIM25. Ubiquitination of ectopically expressed RIG-I-2Cards domain was decreased by RSV infection, indicating that RSV possesses ability to inhibit TRIM25-mediated RIG-I ubiquitination. Similarly, ectopic expression of NS1 sufficiently suppressed TRIM25-mediated RIG-I ubiquitination. Furthermore, interaction between NS1 and TRIM25 was detected by a co-immunoprecipitation assay. Further biochemical assays showed that the SPRY domain of TRIM25, which is responsible for interaction with RIG-I, interacted sufficiently with NS1. Suppression of RIG-I ubiquitination by NS1 resulted in decreased interaction between RIG-I and its downstream molecule, MAVS. The suppressive effect of NS1 on RIG-I signaling could be abrogated by overexpression of TRIM25. Collectively, this study suggests that RSV NS1 interacts with TRIM25 and interferes with RIG-I ubiquitination to suppress type-I interferon signaling.
Highlights
Respiratory syncytial virus (RSV) belongs to the family Pneumoviridae and contains a negative-sense single-stranded RNA genome
We explored the possibility that NS1 proteins of RSV interfere with tripartite motif-containing protein 25 (TRIM25)-mediated Retinoic acid inducible gene-I (RIG-I) ubiquitination to dissect the molecular mechanism underlying the direct inhibition of RIG-I signaling by NS1/2 of RSV
TRIM25-mediated is an anessential essentialstep stepforfor successful induction of RIG-I-mediated antiviral responses, we explored the possibility that induction of RIG-I-mediated antiviral responses, we explored the possibility that RSV suppresses
Summary
Respiratory syncytial virus (RSV) belongs to the family Pneumoviridae and contains a negative-sense single-stranded RNA genome. Viruses 2018, 10, 716 of mitochondrial antiviral signaling protein (MAVS) and myeloid differentiation primary response (MyD88), which are crucial downstream molecules of RIG-I signaling and TLR signaling, respectively, resulted in an increased viral load in mice, indicating the role of RIG-I and TLR signaling pathways against RSV infection [6]. Since TRIM25 plays a crucial role in RIG-I signaling pathways, several viral proteins target TRIM25 to evade RIG-I-mediated antiviral responses [9]. The NS1 and NS2 of RSV are capable of inducing the degradation of key molecules in RIG-I signaling and type-I interferon signaling including RIG-I, IRF3, IRF7, TBK1 and STAT2, to suppress antiviral responses by forming a large degradative complex [17]. We explored the possibility that NS1 proteins of RSV interfere with TRIM25-mediated RIG-I ubiquitination to dissect the molecular mechanism underlying the direct inhibition of RIG-I signaling by NS1/2 of RSV
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