Although reticulophagy, the selective autophagy of the endoplasmic reticulum (ER), restricts several RNA viruses, whether this pathway constrains DNA virus infection remains unknown. Recently, we found that FAM134B (family with sequence similarity 134 member B), an ER-resident cargo receptor that mediates reticulophagy, restricts African swine fever virus (ASFV), a large cytoplasmic DNA virus, by targeting the major capsid proteins p72 and pA137R for lysosomal degradation, thereby blocking capsid assembly at perinuclear viral factories. ASFV counters this restriction through the virulence factor pMGF300-2 R encoded by the MGF300-2 R gene of ASFV, which binds to FAM134B, recruits LC3B (microtubule-associated protein 1 light chain 3 beta), an ATG8 (autophagy-related protein 8) family member, via the C-terminal LC3-interacting region (LIR) motif, and directs FAM134B into autophagic degradation. Deletion of the MGF300-2 R gene in the ASFV genome restores FAM134B abundance, reduces viral replication, and attenuates virulence in pigs. These findings establish reticulophagy as a previously unrecognized antiviral barrier against a large DNA virus and reveal a host-virus arms race centered on the reticulophagy receptor.

Keywords: African swine fever virus; FAM134B; pMGF300-2R; reticulophagy; viral factories.