Membralin Selects Foreign Glycoproteins from the Endoplasmic Reticulum to Lysosomes for Degradation

The endoplasmic reticulum (ER) plays a central role in protein synthesis and folding. Membralin is a multi-pass membrane protein involved in ER-associated degradation (ERAD). Here, we demonstrate that Membralin assembles a protein degradation machinery across the ER membrane, specifically targeting class I fusion proteins expressed by major human viruses. Membralin interacts with MAN1B1 and p97/VCP through its luminal and cytoplasmic loops, respectively. Importantly, Membralin also contains an LC3-interacting region (LIR) in its cytoplasmic tail. The expression of these viral glycoproteins induces ER stress, prompting MAN1B1 to trim mannose residues extensively. Subsequently, Membralin recruits p97/VCP and initiate ER-phagy via its LIR, leading to degradation. This pathway specifically recognizes dense N -glycans and is selective, as it does not degrade misfolded domestic proteins. Collectively, our study reveals a cell-autonomous immunity inside the ER orchestrated by Membralin, underscoring its important role in the clearance of foreign glycoproteins to maintain cellular homeostasis.