Protein quality control in the endoplasmic reticulum (ER) maintains proteostasis by eliminating aberrant or foreign proteins through ER-associated degradation (ERAD) or ER-to-lysosome-associated degradation (ERLAD). Here, Membralin (TMEM259) is identified as a previously unrecognized ER-phagy receptor that assembles a selective degradation machinery targeting viral class I fusion glycoproteins. Membralin recruits MAN1B1, an α-mannosidase that trims high-mannose N-glycans, through its luminal loop, and VCP/p97 through its cytoplasmic loop, while its cytoplasmic tail contains a functional LC3-interacting region (LIR) essential for autophagic delivery. This Membralin-MAN1B1-VCP axis directs viral glycoproteins su... More
Protein quality control in the endoplasmic reticulum (ER) maintains proteostasis by eliminating aberrant or foreign proteins through ER-associated degradation (ERAD) or ER-to-lysosome-associated degradation (ERLAD). Here, Membralin (TMEM259) is identified as a previously unrecognized ER-phagy receptor that assembles a selective degradation machinery targeting viral class I fusion glycoproteins. Membralin recruits MAN1B1, an α-mannosidase that trims high-mannose N-glycans, through its luminal loop, and VCP/p97 through its cytoplasmic loop, while its cytoplasmic tail contains a functional LC3-interacting region (LIR) essential for autophagic delivery. This Membralin-MAN1B1-VCP axis directs viral glycoproteins such as SARS-CoV-2 spike, Ebola GP, influenza HA, and HIV-1 Env to lysosomes for degradation independently of polyubiquitination or canonical ER-phagy receptors. In contrast, misfolded host glycoproteins are degraded through conventional ERAD or FAM134B-dependent ERLAD pathways. Mechanistically, the Membralin complex selectively recognizes densely glycosylated substrates, likely by sensing clustered N-glycans characteristic of viral envelope proteins. Loss of Membralin or MAN1B1 markedly enhances pseudoviral infectivity, underscoring its antiviral role. These findings reveal a ubiquitin-independent ERLAD pathway that discriminates foreign from host glycoproteins and establish Membralin as a central scaffold coordinating ER quality control and innate antiviral defense.
