Protein M of NADC30-like PRRSV induces MARCH6-mediated K33-linked polyubiquitination of SLA-DRA

NADC30-like porcine reproductive and respiratory syndrome virus (PRRSV) has replaced the high-pathogenicity PRRSV (HP-PRRSV) as the predominant circulating strain in China. Unlike HP-PRRSV, NADC30-like PRRSV exhibits increased genetic diversity and enhanced persistence for persistent infection, along with altered host immune responses, which collectively complicate disease control. In this study, we found that infection with the NADC30-like representative strain XM2020 induced a weaker antibody response than infection with the HP-PRRSV strain HuB2, and that SLA-DRA expression was downregulated. In vitro analyses further demonstrated that this suppression of SLA-DR in PBMCs is independently of viral replication. Mechanistically, XM2020-M binds to SLA-DRA and recruits the E3 ubiquitin ligase MARCH6, promoting K33-linked polyubiquitination and proteasomal degradation of SLA-DRA, a function not observed for HuB2-M. In addition, XM2020-M stabilizes MARCH6 by inhibiting its degradation, thereby enhancing its ubiquitin ligase activity. Further mapping identified residue 93 of XM2020-M as a critical determinant of this process. Collectively, these findings reveal a novel immune evasion mechanism by which XM2020-M impairs antigen presentation by targeting the degradation of SLA-DRA, which may contribute to altered adaptive immune responses and viral persistence associated with NADC30-like strains.