Rui Huang,Cui-Hong Rao,Yuan-Zhe Bai,Changqing Yu,Meng Chen,Jin-Mei Peng,Shi-Jia Xu,Yue Sun,Meng Fandan,Chuang Lyu,Mirwaise Khan,Tong-Qing An,Zhi-Jun Tian,Xue-Hui Cai,Gang Wang,Yan-Dong Tang

Vet Microbiol. 2024 Jun 22:295:110164.doi: 10.1016/j.vetmic.2024.110164. Online ahead of print.

Abstract

The membrane-associated RING-CH (MARCH) family of proteins are members of the E3 ubiquitin ligase family and are essential for a variety of biological functions. Currently, MARCH proteins are discovered to execute antiviral functions by directly triggering viral protein degradation or blocking the furin cleavage of viral class I fusion proteins. Here, we report a novel antiviral mechanism of MARCH1 and MARCH2 (MARCH1/2) in the replication of Pseudorabies virus (PRV), a member of the Herpesviridae family. We discovered MARCH1/2 restrict PRV replication at the cell-to-cell fusion step. Furthermore, MARCH1/2 block gB cleavage, and this is dependent on their E3 ligase activity. Interestingly, the blocking of gB cleavage by MARCH1/2 does not contribute to their antiviral activity in vitro. We discovered that MARCH1/2 are associated with the cell-to-cell fusion complex of gB, gD, gH, and gL and trap these viral proteins in the trans-Golgi network (TGN) rather than degrading them. Overall, we conclude that MARCH1/2 inhibit PRV by trapping the viral cell-to-cell fusion complex in TGN.

Keywords: Cell-to-cell fusion; Furin; Glycoprotein B; Herpesvirus; MARCH1; MARCH2; Pseudorabies virus.