RETREG1/FAM134B-mediated micro-ER-phagy in the retrovirus–SERINC5 arms race

Reticulophagy regulator 1 (RETREG1)/Family with sequence similarity 134 member B (FAM134B) is a selective endoplasmic reticulum (ER)-phagy receptor that mediates starvation-induced macro-ER-phagy, but whether it participates in other pathways mediating ER turnover has remained unclear. Here, we unveil a previously unrecognized role for RETREG1 in micro-ER-phagy and show how the murine leukemia virus (MLV) accessory protein glycosylated group-specific antigen (glycoGag) exploits this pathway to antagonize the host restriction factor SERINC5 (serine incorporator 5). GlycoGag binds SERINC5 in the endoplasmic reticulum (ER) and selectively recruits RETREG1 to eliminate SERINC5 through an autophagosome-independent process that bypasses ATG3 (autophagy-related), ATG5, ATG7, BECN1 (Beclin-1), LC3 (microtubule-associated protein 1 light chain 3) lipidation, and PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3)/hVPS34 (vacuolar protein sorting 34). RETREG1 knockout abolishes degradation of ER-retained SERINC5, whereas endolysosomal turnover of surface SERINC5 remains partially intact, demonstrating that glycoGag utilizes dual ER-phagy and endolysosomal routes to suppress SERINC5. These findings expand the functional repertoire of RETREG1 in autophagy, identify that retroviruses repurpose micro-ER-phagy to circumvent SERINC5-mediated restriction, and reveal ER-phagy as an understudied battleground in the ongoing arms race between cellular restriction factors and viral accessory proteins.