TRIM7 Inhibits Rabies Virus Replication by Promoting K48-Linked Ubiquitination and Degradation of RABV-M

Rabies virus (RABV) can infect almost all warm-blooded animals, with a 100% mortality rate once clinical symptoms develop. With no specific therapeutic drugs currently available, rabies remains a major public health threat globally. Triple-motif protein 7 (TRIM7), a member of the TRIM family, plays a crucial role in the innate immune response against viral infections. However, the function of TRIM7 during RABV infection remains unknown. This study identified several differentially expressed TRIM proteins in RABV-infected mouse neuroblastoma (NA) cells through RNA-seq analysis. TRIM7 was found to be upregulated in RABV-infected cells compared to uninfected cells. Knockdown of TRIM7 promoted RABV replication. In contrast, overexpression of TRIM7 significantly inhibited RABV replication and prolonged the lethal time of RABV in suckling mice, which was reversed by a proteasome inhibitor. Further investigation revealed a direct interaction between TRIM7 and RABV matrix protein (M). TRIM7 inhibited viral replication by promoting K48-linked ubiquitination and degradation of RABV-M. Additionally, lysine 115 (K115) in RABV-M was identified as a common site for TRIM7-induced ubiquitination and degradation of M. Collectively, our work demonstrates that TRIM7 inhibits RABV replication by promoting ubiquitination and degradation of RABV-M, providing a novel therapeutic target for rabies treatment.