TRIM14 restricts tembusu virus infection through degrading viral NS1 protein and activating type I interferon signaling.

Abstract

Tembusu virus (TMUV), an emerging avian orthoflavivirus, causes severe economic losses due to egg-drop syndrome and fatal encephalitis in domestic waterfowl. To combat this threat, the host immune system plays a crucial role in controlling and eliminating TMUV infection. Understanding the mechanisms of this immune response is thus vital for developing effective strategies against the virus. In this study, we investigated the antiviral activities of duck TRIM family proteins (duTRIM) against TMUV, focusing particularly on duTRIM14 as a potent host restriction factor. We showed that overexpression of duTRIM14 significantly inhibits TMUV replication, while its deficiency leads to increased viral titers. We elucidate a novel mechanism by which duTRIM14 interacts with the TMUV NS1 protein, facilitating its K27/K29-linked polyubiquitination and subsequent proteasomal degradation. The Lys141 residue on NS1 was identified as critical for this process, with its removal significantly enhancing TMUV replication both in vitro and in vivo. Furthermore, we showed that duTRIM14 interacts with duck TBK1 (duTBK1), promoting its K63-linked polyubiquitination on Lys30 and Lys401, which substantially augments IFN-β production during TMUV infection. Taken together, these results provide a novel dual-action antiviral mechanism in which duTRIM14 suppresses TMUV replication by simultaneously promoting proteasomal degradation of NS1 and enhancing the host antiviral response by modulating duTBK1 activity.