Membralin Assembles a MAN1B1–VCP Complex to Target Foreign Glycoproteins from the Endoplasmic Reticulum to Lysosomes for Degradation

Abstract 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.