Murine leukemia virus glycoGag antagonizes SERINC5 via ER-phagy receptor RETREG1

Serine incorporator 5 (SERINC5) is a host restriction factor that inhibits the infectivity of certain enveloped viruses, including human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus (MLV), by incorporating into the viral envelope and blocking viral entry. To counteract this, HIV-1 and MLV encode accessory proteins-Nef and glycoGag, respectively-that downregulate SERINC5 expression in producer cells. Here, we demonstrate that glycoGag employs more complex and effective mechanisms than Nef to antagonize SERINC5. Despite being a type II integral membrane protein, glycoGag primarily localizes to the cytoplasm, while Nef is mainly associated with the plasma membrane. Additionally, glycoGag is rapidly degraded by proteasomes, in contrast to the greater stability of Nef, and becomes stabilized after binding to SERINC5. While both proteins downregulate SERINC5 at the cell surface, glycoGag also targets SERINC5 at the endoplasmic reticulum (ER). We further show that this ER-specific downregulation is mediated by reticulophagy regulator 1 (RETREG1), an ER-phagy receptor, through micro-ER-phagy. These findings reveal that retroviruses hijack a selective autophagy pathway to counteract host restriction and promote productive infection.