Tripartite motif-containing 34 (TRIM34) protein interacts with the nucleocytoplasmic transport machinery and negatively modulates antiviral responses

The tripartite motif-containing (TRIM) 34 protein is an interferon (IFN)-induced protein whose expression is upregulated after influenza A virus (IAV) infection. Here, we identify a previously unknown function for TRIM34 as a negative regulator of innate immune responses following IFN treatment and IAV infection, even in mice, suggesting that this effect is broad and conserved. Complementary overexpression and silencing experiments in cultured cells show that TRIM34 expression positively correlates with IAV titers, indicating that TRIM34 promotes viral replication, likely by counteracting antiviral responses. Moreover, we show novel interactions of TRIM34 with cellular proteins involved in the nucleocytoplasmic transport of host mRNAs and proteins, even in mock-infected cells. Remarkably, these TRIM34 interactions seem independent of TRIM34 E3 ubiquitin ligase activity and affect the nuclear import of IFN-regulatory factor 3 (IRF3) and the nuclear export of host mRNAs encoding antiviral functions, without affecting the nuclear export of viral mRNAs. These results provide a likely mechanism by which TRIM34 dampens host innate immune responses. These TRIM34-mediated effects could be further exploited to develop new antiviral drugs against IAV, and potentially other viral infections.