PRRSV nsp12-mediated autophagic degradation of SLA-I-HC requires the crucial involvement of ATG5

Porcine reproductive and respiratory syndrome virus (PRRSV) subverts porcine innate and adaptive immunity, however, the molecular basis of underlying its interference with antigen presentation remains undefined. Herein, we demonstrate that PRRSV infection selectively depletes cell-surface swine leukocyte antigen class I (SLA-I), a heterodimer consisting of a polymorphic glycosylated heavy chain (SLA-I-HC) and β2-microglobulin, thereby abrogating SLA-I-restricted antigen presentation. The viral non-structural protein 12 (nsp12) is both necessary and sufficient for this phenotype. Mechanistically, nsp12 triggers ATG5 (autophagy related 5)-dependent autophagy and concurrently nucleates a ternary complex with SLA-I-HC and ATG5, redirecting SLA-I-HC to autolysosomes for degradation. Phosphorylation of ATG5 at threonine 101 is indispensable for nsp12-mediated SLA-I-HC turnover. These findings identify nsp12 as the first PRRSV-encoded factor that hijacks selective autophagy to disrupt the SLA-I antigen presentation axis, providing mechanistic insights into viral immune evasion.