HnRNPC triggers the degradation of MITA to suppress the interferon-mediated antiviral response

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of 34-120 kDa nuclear proteins that have recently been reported to participate in virus replication. The hnRNP family contains approximately 20 members, including hnRNP A1, hnRNP A2, hnRNP A2B1, hnRNPC, hnRNPD and hnRNPK. HnRNPC plays important roles in RNA biology, including expression, stability, mRNA splicing, nonspecific sequence export and 3'-end processing; however, the mechanisms underlying hnRNPC regulatory roles are not fully understood. Here, we found that zebrafish hnRNPC promoted spring viraemia of carp virus (SVCV) replication by increasing the stability of SVCV phosphoprotein while inhibiting the K48-linked ubiquitination of virus phosphoprotein, thereby suppressing the type I interferon (IFN) response. Mechanistically, hnRNPC could interact with the mediator of IFN regulatory factor 3 activation (MITA) to activate K48-linked ubiquitination for MITA degradation through the C-terminal domain of hnRNPC. We also showed that human hnRNPC could interact with MITA and that the overexpression of human hnRNPC decreased MITA protein in HEK293 cells, suggesting that the negative regulatory effects of hnRNPC on the type I IFN response are evolutionarily conserved. Collectively, our data indicate that hnRNPC promotes virus replication by suppressing IFN production activated by MITA and increasing the availability of viral proteins. Our work reveals an evolutionarily conserved mechanism that controls the IFN-mediated antiviral response by a member of the hnRNP family in vertebrates.