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 de

SUBMITTER: Zhang J 

PROVIDER: S-EPMC12904022 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature