Guanylate Binding Protein 4 Negatively Regulates Virus-Induced Type I IFN and Antiviral Response by Targeting IFN Regulatory Factor 7

Abstract

IRF7 is known as the master regulator in virus-triggered induction of type I IFNs (IFN-I). In this study, we identify GBP4 virus-induced protein interacting with IRF7 as a negative regulator for IFN-I response. Overexpression of GBP4 inhibits virus-triggered activation of IRF7-dependent signaling, but has no effect on NF-κB signaling, whereas the knockdown of GBP4 has opposite effects. Furthermore, the supernatant from Sendai virus-infected cells in which GBP4 have been silenced inhibits the replication of vesicular stomatitis virus more efficiently. Competitive coimmunoprecipitation experiments indicate that overexpression of GBP4 disrupts the interactions between TRAF6 and IRF7, resulting in impaired TRAF6-mediated IRF7 ubiquitination. Our results suggest that GBP4 is a negative regulator of virus-triggered IFN-I production, and it is identified as a novel protein targeting IRF7 and inhibiting its function.

Functions of the two zebrafish MAVS variants are opposite in the induction of IFN1 by targeting IRF7

“…Several reports demonstrated that IRF7 is negatively regulated by different mechanisms. Guanylate binding protein 4 (GBP4) disrupts the interactions between TRAF6 and IRF7, leading to reduction of TRAF6-mediated IRF7 ubiquitination [42]. Tripartite motif-containing protein 28 (TRIM28) mediates SUMOylation (post-translational modification mediated by small ubiquitin-like modifier (SUMO) proteins) of IRF7 and inhibits IRF7 transactivation activity [43].…”

Negative Regulation of Nmi on Virus-Triggered Type I IFN Production by Targeting IRF7

“…The IFN bioassay was performed as described previously (20). In brief, supernatants from SeV-infected RAW264.7 cells were overlaid onto L929 cells seeded in a 48-well plate.…”

“…Polyclonal Ab to Nmi (anti-Nmi) was generated by immunization of rabbits with full-length Nmi expressed by Escherichia coli. Polyclonal Ab to IRF7 (anti-IRF7) was generated as described previously (20). SeV was provided by Wuhan Institutes of Virology, Chinese Academy of Sciences (Shanghai, China).…”

“…HA-K48-ubi and HA-K63-ubi plasmids were kindly provided by Hongbing Shu (Wuhan University, Wuhan, China). Other plasmids were generated or obtained as described before (20). Polyclonal Ab to Nmi (anti-Nmi) was generated by immunization of rabbits with full-length Nmi expressed by Escherichia coli.…”

“…Although it is essential for activating the innate immune response and enhancing adaptive immunity against viruses, the host antiviral response must be tightly controlled to prevent harmful effects resulting from excessive activation. Several molecules have been reported to regulate the virus-triggered signaling pathway, including A20, Pin1, SIKE, RNF125, DUBA, DAK, TBK1s, MIP-T3, Trim28, NLRX1, ABIN1, ARL16, PIASy, and GBP4 (18)(19)(20)(21)(22)(23)(24)(25). All of these molecules target distinct components using specific mechanisms.…”