RACK1 degrades MAVS to promote bovine ephemeral fever virus replication via upregulating E3 ubiquitin ligase STUB1

Abstract

Receptors for activated C kinase 1 (RACK1) could competitively combine with mitochondrial antiviral signaling protein (MAVS) to inhibit the type I interferon (IFN) signaling pathway during viral infection in vitro. However, whether RACK1 can degrade MAVS to enhance viral replication is still unknown. In this study, we found that bovine epidemic fever virus (BEFV) infection triggered the expression of RACK1. Overexpression of RACK1 promoted BEFV replication, while knockdown of RACK1 inhibited the replication of BEFV. Further research showed that RACK1 inhibited the type I IFN signaling pathway during BEFV infection by degrading MAVS, and RACK1 degraded MAVS via the ubiquitin-proteasome system. Mechanistically, RACK1 up-regulated the expression of E3 ubiquitin ligase STIP1 homology and U-box containing protein 1 (STUB1), thereby promoting the ubiquitination and degradation of MAVS. In addition, RACK1 degraded MAVS by enhancing the interaction between STUB1 and MAVS but not via its interaction with STUB1. Overall, our study reveals a novel mechanism by which RACK1 inhibits the type I IFN signaling pathway to BEFV infection through degradation of MAVS, thereby promoting viral infection. These findings provide a new perspective for the MAVS degradation regulated by RACK1.

Keywords: Bovine ephemeral fever virus (BEFV); Mitochondrial antiviral signaling protein (MAVS); Receptor for activated C kinase 1 (RACK1); Virus replication.