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Here, Membralin (TMEM259) is identified as a previously unrecognized ER\u2010phagy receptor that assembles a selective degradation machinery targeting viral class I fusion glycoproteins. Membralin recruits MAN1B1, an \u03b1\u2010mannosidase that trims high\u2010mannose N\u2010glycans, through its luminal loop, and VCP\/p97 through its cytoplasmic loop, while its cytoplasmic tail contains a functional LC3\u2010interacting region (LIR) essential for autophagic delivery. This Membralin\u2013MAN1B1\u2013VCP axis directs viral glycoproteins such as SARS\u2010CoV\u20102 spike, Ebola GP, influenza HA, and HIV\u20101 Env to lysosomes for degradation independently of polyubiquitination or canonical ER\u2010phagy receptors. In contrast, misfolded host glycoproteins are degraded through conventional ERAD or FAM134B\u2010dependent ERLAD pathways. Mechanistically, the Membralin complex selectively recognizes densely glycosylated substrates, likely by sensing clustered N\u2010glycans characteristic of viral envelope proteins. Loss of Membralin or MAN1B1 markedly enhances pseudoviral infectivity, underscoring its antiviral role. These findings reveal a ubiquitin\u2010independent ERLAD pathway that discriminates foreign from host glycoproteins and establish Membralin as a central scaffold coordinating ER quality control and innate antiviral defense.<\/jats:p>","DOI":"10.1002\/advs.202519256","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T14:51:16Z","timestamp":1764600676000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Membralin Assembles a MAN1B1\u2013VCP Complex to Target Foreign Glycoproteins from the Endoplasmic Reticulum to Lysosomes for Degradation"],"prefix":"10.1002","volume":"13","author":[{"given":"Jing","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory for Animal Disease Control and Prevention Harbin Veterinary Research Institute Chinese Academy of Agricultural Sciences Harbin 150069 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