HACE1 Negatively Regulates Virus-Triggered Type I IFN Signaling by Impeding the Formation of the MAVS-TRAF3 Complex.

He-Ting Mao,Yu Pan,Jun Zhang,Yan Wang,Yu Zhou,Xiao-Ping Qian,Juan Cai,Jun-Ling Meng,Yu Zhang

doi:10.3390/v8050146

He-Ting Mao, Yu Pan + Show 7 more

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https://doi.org/10.3390/v8050146

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Abstract

During virus infection, the cascade signaling pathway that leads to the production of proinflammatory cytokines is controlled at multiple levels to avoid detrimental overreaction. HACE1 has been characterized as an important tumor suppressor. Here, we identified HACE1 as an important negative regulator of virus-triggered type I IFN signaling. Overexpression of HACE1 inhibited Sendai virus- or poly (I:C)-induced signaling and resulted in reduced IFNB1 production and enhanced virus replication. Knockdown of HACE1 expression exhibited the opposite effects. Ubiquitin E3 ligase activity of the dead mutant HACE1/C876A had a comparable inhibitory function as WT HACE1, suggesting that the suppressive function of HACE1 on virus-induced signaling is independent of its E3 ligase activity. Further study indicated that HACE1 acted downstream of MAVS and upstream of TBK1. Mechanistic studies showed that HACE1 exerts its inhibitory role on virus-induced signaling by disrupting the MAVS-TRAF3 complex. Therefore, we uncovered a novel function of HACE1 in innate immunity regulation.

Highlights

To initiate an effective antiviral response, RNA viruses are recognized by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and trigger multiple signaling pathways to promote the production of proinflammatory cytokines, including type I IFNs [1,2,3,4]
We demonstrate for the first time that HACE1 contributes to negative regulation of the virus-induced type I IFN signaling via disrupting the MAVS-TRAF3 complex
I IFN signaling by the dual-luciferase reporter, we identified HACE1 as a potential negative regulator in this pathway

Summary

Introduction

To initiate an effective antiviral response, RNA viruses are recognized by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and trigger multiple signaling pathways to promote the production of proinflammatory cytokines, including type I IFNs [1,2,3,4]. We have had great interest in the identification of the essential regulators in this signaling pathway. This will provide potential therapeutic intervention and targets for infection, inflammation or autoimmune diseases in the future. Except LGP2, both RIG-I and MDA5 contain a caspase recruitment domain (CARD) that is indispensable for downstream protein-protein interactions. The activated RIG-I undergoes self-dimerization and structural changes that permit the CARD domain of RIG-I to interact with the CARD domain of downstream essential adaptor protein

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