Abstract
VISA (also known as MAVS, IPS-1 and Cardif) is an essential adaptor protein in innate immune response to RNA virus. The protein level of VISA is delicately regulated before and after viral infection to ensure the optimal activation and timely termination of innate antiviral response. It has been reported that several E3 ubiquitin ligases can mediate the degradation of VISA, but how the stability of VISA is maintained before and after viral infection remains enigmatic. In this study, we found that the ER-associated inactive rhomboid protein 2 (iRhom2) plays an essential role in mounting an efficient innate immune response to RNA virus by maintaining the stability of VISA through distinct mechanisms. In un-infected and early infected cells, iRhom2 mediates auto-ubiquitination and degradation of the E3 ubiquitin ligase RNF5 and impairs the assembly of VISA-RNF5-GP78 complexes, thereby antagonizes ER-associated degradation (ERAD) of VISA. In the late phase of viral infection, iRhom2 mediates proteasome-dependent degradation of the E3 ubiquitin ligase MARCH5 and impairs mitochondria-associated degradation (MAD) of VISA. Maintenance of VISA stability by iRhom2 ensures efficient innate antiviral response at the early phase of viral infection and ready for next round of response. Our findings suggest that iRhom2 acts as a checkpoint for the ERAD/MAD of VISA, which ensures proper innate immune response to RNA virus.
Highlights
Innate immune response provides the first line of host defense against invading microbial pathogens[1]
Our findings suggest that inactive rhomboid protein 2 (iRhom2) acts as a checkpoint for the ER-associated degradation (ERAD)/mitochondria-associated degradation (MAD) of VISA, which ensures proper innate immune response to RNA virus
VISA is a central adaptor in innate immune response to RNA virus, which is down-regulated by multiple ubiquitination-dependent mechanisms
Summary
Innate immune response provides the first line of host defense against invading microbial pathogens[1]. Binding of viral RNAs to RIG-I and MDA5 induces their conformational changes and recruitment to the mitochondrial membrane-located adaptor protein VISA ( called MAVS, IPS-1 and Cardif)[3,4,5,6]. This triggers the formation of large prion-like VISA polymers, which in turn serve as platforms for recruitment of TRAF2/3/5/6 through its TRAF-binding motifs[7,8]. The TRAF proteins further recruit TBK1 and the IKK complex to phosphorylate IRF3 and IκBα respectively, leading to activation of IRF3 and NF-κB and induction of downstream antiviral effectors
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