Grass Carp Mex3A Promotes Ubiquitination and Degradation of RIG-I to Inhibit Innate Immune Response

Abstract

As one of the Mex3 family members, Mex3A is crucial in cell proliferation, migration, and apoptosis in mammals. In this study, a novel gene homologous to mammalian Mex3A (named CiMex3A, MW368974) was cloned and identified in grass carp, which is 1,521 bp in length encoding a putative polypeptide of 506 amino acids. In CIK cells, CiMex3A is upregulated after stimulation with LPS, Z-DNA, and especially with intracellular poly(I:C). CiMex3A overexpression reduces the expressions of IFN1, ISG15, and pro-inflammatory factors IL8 and TNFα; likewise, Mex3A inhibits IRF3 phosphorylation upon treatment with poly(I:C). A screening test to identify potential targets suggested that CiMex3A interacts with RIG-I exclusively. Co-localization analysis showed that Mex3A and RIG-I are simultaneously located in the endoplasmic reticulum, while they rarely appear in the endosome, mitochondria, or lysosome after exposure to poly(I:C). However, RIG-I is mainly located in the early endosome and then transferred to the late endosome following stimulation with poly(I:C). Moreover, we investigated the molecular mechanism underlying CiMex3A-mediated suppression of RIG-I ubiquitination. The results demonstrated that Mex3A truncation mutant (deletion in the RING domain) can still interact physically with RIG-I, but fail to degrade it, suggesting that Mex3A also acts as a RING-type E3 ubiquitin ligase. Taken together, this study showed that grass carp Mex3A can interact with RIG-I in the endoplasmic reticulum following poly(I:C) stimulation, and then Mex3A facilitates the ubiquitination and degradation of RIG-I to inhibit IRF3-mediated innate antiviral immune response.

Activation of insulin-like growth factor-1 receptor (IGF-1R) promotes growth of colorectal cancer through triggering the MEX3A-mediated degradation of RIG-I

“…However, the effects of RIG-I therapy can be influenced by numerous factors. Previous studies identified a negative correlation between RIG-I and MEX3A in tumorigenesis 47 , 49 . MEX3A, an RNA-binding protein (RBP), post-transcriptionally regulates a number of biological processes, including tumor immunologically relevant ones, thereby, leading to the immune evasion of tumor cells.…”

VP4/VP56/VP35 Virus-like Particles Effectively Protect Grass Carp (Ctenopharyngodon idella) against GCRV-II Infection

“…The rapid upregulation of IL-1β and TNFα mRNA expression in the APS–Vaccine group suggests that the treatment could more effectively mitigate the inflammatory response. IFN1 plays a crucial role in the host’s defense against viruses, and a significant increase in its mRNA expression levels was observed in the kidney after vaccination [ 50 , 51 ]. In our research, we noticed an upregulated trend at various time points for the mRNA expression of IFN1 and IFN-γ2 in the APS–Vaccine group, which illustrates the effective improvement in both cellular and humoral immunity to defend against GCRV infection in grass carp.…”

Ring-finger protein 34 facilitates nervous necrosis virus evading antiviral innate immunity by targeting TBK1 and IRF3 for ubiquitination and degradation

“…The RING domain is the critical functional domain for RING finger family E3 ubiquitin ligases. Truncation mutation within RING domain abolished the ability of Mex3A to induce the ubiquitination and degradation of RIG-I [28]. TRIM40 mutant lacking RING domain greatly impaired its inhibition on IFN-b promoter activity [5].…”