Feline Calicivirus Proteinase-Polymerase Degrades mRNAs to Inhibit Host Gene Expression.

Wu, Hongxia; Huang, Jiapei; Liu, Yongxiang; Pan, Yudi; Li, Yin; Miao, Qian; Qu, Liandong; Tian, Jin

To replicate efficiently and evade the antiviral immune response of the host, some viruses degrade host mRNA to induce host gene shutoff via encoding shutoff factors. In this study, we found that feline calicivirus (FCV) infection promotes the degradation of endogenous and exogenous mRNAs and induces host gene shutoff, which results in global inhibition of host protein synthesis. Screening assay revealed that proteinase-polymerase (PP) is a most effective factor in reducing mRNA expression. Moreover, differently virulent strains of FCV PP could induce mRNA degradation. Further, we found that the key sites of the PP protein required for its proteinase activity are also essential for its shutoff activity, but also required for viral replication. The mechanism analysis showed that PP mainly targets Pol II-transcribed RNA in a ribosome-, 5'cap- and 3' poly(A) tail-independent manner. Moreover, the purified GST-PP fusion protein exhibits ribonuclease activity in vitro in assays using GFP RNA transcribed in vitro as substrates in the absence of other viral or cellular proteins. Finally, PP-induced shutoff requires host Xrn1 to complete further RNA degradation. This study provides a newly discovered strategy in which FCV PP protein induces host gene shutoff by promoting the degradation of host mRNAs.ImportanceVirus infection-induced shutoff is the result of targeted or global manipulation of cellular gene expression and leads to efficient viral replication and immune evasion. FCV is a highly contagious pathogen that persistently infects cats. It is unknown how FCV blocks the host immune response and persistently exists in cats. In this study, we found that FCV infection promotes the degradation of host mRNAs and induces host gene shutoff via a common strategy. Further, PP protein for different FCV strains is a key factor that enhances mRNA degradation. An in vitro assay showed that the GST-PP fusion protein possess ribonuclease activity in the absence of other viral or cellular proteins. This study demonstrates that FCV induces host gene shutoff by promoting the degradation of host mRNAs, thereby introducing a potential mechanism by which FCV infection inhibits the immune response.