The tripartite motif (
TRIM) protein family comprises more than 60 members that have diverse functions in various biological processes. Although a small number of
TRIM proteins have been shown to regulate innate immunity, much remains to be learned about the functions of the majority of the
TRIM proteins. Here we identify TRIM56 as a cellular
protein associated with the N-terminal
protease (N(pro)) of bovine viral
diarrhea virus (BVDV), a pestiviral
interferon antagonist which degrades
interferon regulatory factor 3 (IRF3) through the
proteasome. We found that TRIM56 was constitutively expressed in most tissues, and its abundance was further upregulated moderately by
interferon or virus. The manipulation of TRIM56 abundance did not affect the
protein turnover of N(pro) and IRF3. Rather, ectopic expression of TRIM56 substantially impaired, while knockdown of TRIM56 expression greatly enhanced, BVDV replication in cell culture. The
antiviral activity of TRIM56 depended on its
E3 ubiquitin ligase activity as well as the integrity of its C-terminal region but was not attributed to a general augmentation of the
interferon antiviral response. Overexpression of TRIM56 did not inhibit the replication of
vesicular stomatitis virus or hepatitis C virus, a virus closely related to BVDV. Together, our data demonstrate that TRIM56 is a novel
antiviral host factor that restricts
pestivirus infection.