Grass carp reovirus VP56 represses interferon production by degrading phosphorylated IRF7

Abstract

Grass carp reovirus (GCRV) is an efficient pathogen causing high mortality in grass carp, meanwhile, fish interferon (IFN) is a powerful cytokine enabling host cells to establish an antiviral state; therefore, the strategies used by GCRV to escape the cellular IFN response need to be investigated. Here, we report that GCRV VP56 inhibits host IFN production by degrading the transcription factor IFN regulatory factor 7 (IRF7). First, overexpression of VP56 inhibited the IFN production induced by the polyinosinic-polycytidylic acid (poly I:C) and mitochondrial antiviral signaling protein (MAVS), while the capacity of IRF7 on IFN induction was unaffected. Second, VP56 interacted with RLRs but did not affect the stabilization of the proteins in the normal state, while the phosphorylated IRF7 activated by TBK1 was degraded by VP56 through K48-linked ubiquitination. Finally, overexpression of VP56 remarkably reduced the host cellular ifn transcription and facilitated viral proliferation. Taken together, our results demonstrate that GCRV VP56 suppresses the host IFN response by targeting phosphorylated IRF7 for ubiquitination and degradation.

Grass Carp Reovirus VP56 Allies VP4, Recruits, Blocks, and Degrades RIG-I to More Effectively Attenuate IFN Responses and Facilitate Viral Evasion

“…IRF3/7 are crucial IFN regulation factors. In a previous report, GCRV VP56 represses IFN production by degrading phosphorylated IRF7 ( 11 ). In the present study, we found that VP56 targets and degrades the immune initial point molecule RIG-I ( Fig.…”

“…The functions of VP56 when the virus particle attaches to the host cell and after entry into the cell membrane are still unclear. Although several reports have claimed to understand part of the function of GCRV fiber protein, further research is needed ( 11 ).…”

“…Tegument protein UL37 of herpes simplex virus 1 (HSV-1) promotes RIG-I deamidation to inhibit viral dsRNA-triggered RIG-I activation ( 28 ). Nonetheless, there are few studies indicating the function of VP56 in the process of GCRV infection and its immune regulation mechanism related to RIG-I and the downstream IFN response ( 11 ). In the present study, we found that VP56 can bind to the RIG-I helicase domain.…”

Grass Carp Reovirus VP35 Degrades MAVS Through the Autophagy Pathway to Inhibit Fish Interferon Production

“…For SVCV, the P protein competitively inhibits the kinase activity of TBK1, and the N protein degrades MAVS in a ubiquitin–proteasome manner, ultimately subverting the RLR signaling pathway ( 32 , 45 ). For GCRV, our previous studies have revealed that VP41 targets MITA, and VP56 degrades phosphorylated IRF7 ( 46 , 47 ). Our study has demonstrated that another protein of GCRV VP35 also acts on the RLR signaling pathway.…”

Ubiquitination modification: critical regulation of IRF family stability and activity

“…A cystine-and histidine-rich N-terminal domain of RTA is critical for its E3 ligase activity (Yu et al, 2005). GCRV (grass carp reovirus) VP56 blocks the host IFN response and facilitates viral replication by inducing K48-linked ubiquitination and degradation of phosphorylated IRF7 upon GCRV infection (Zhang et al, 2020). In addition to NSP1, IRF9 is targeted by the immediate-early protein ORF63 encoded by VZV and simian varicella virus, which blocks JAK-STAT signaling by degrading IRF9 in a proteasome-dependent manner (Verweij et al, 2015).…”