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Purification of the Membrane Compartment for Endoplasmic Reticulum-associated Degradation of Exogenous Antigens in Cross-presentation
Published on: August 21, 2017
Membralin Assembles a MAN1B1-VCP Complex to Target Foreign Glycoproteins from the Endoplasmic Reticulum to Lysosomes
Jing Zhang1, Xiaoran Lu1, Sunan Li1
1State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China.
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.
Insights
Membralin, a new ER-phagy receptor, targets viral glycoproteins for lysosomal degradation via a unique pathway, enhancing innate antiviral defense. This process discriminates foreign from host proteins, independent of ubiquitination.
Area of Science:
- Cellular Biology
- Immunology
- Virology
Background:
- Endoplasmic reticulum (ER) protein quality control maintains proteostasis via ER-associated degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD).
- Selective autophagy receptors play crucial roles in targeting specific substrates for degradation.
Purpose of the Study:
- To identify novel ER-phagy receptors involved in protein quality control.
- To elucidate the mechanism by which the ER discriminates between foreign and host glycoproteins for degradation.
- To investigate the role of Membralin in innate antiviral defense.
Main Methods:
- Yeast-two-hybrid screening and co-immunoprecipitation to identify interacting proteins.
- CRISPR/Cas9 gene editing to generate knockout cell lines.
- Confocal microscopy and Western blotting to analyze protein localization and degradation.
- Pseudoviral infectivity assays to assess antiviral function.
Main Results:
- Membralin (TMEM259) was identified as a novel ER-phagy receptor that recruits MAN1B1 and VCP/p97.
- The Membralin-MAN1B1-VCP complex mediates the degradation of viral glycoproteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) independently of polyubiquitination.
- This pathway selectively targets viral glycoproteins, distinguishing them from misfolded host glycoproteins degraded by conventional ERAD or FAM134B-dependent ERLAD.
- Loss of Membralin or MAN1B1 increases pseudoviral infectivity, highlighting Membralin's antiviral role.
Conclusions:
- Membralin acts as a crucial scaffold for a ubiquitin-independent ER-to-lysosome-associated degradation pathway.
- This pathway provides innate antiviral defense by selectively degrading foreign viral glycoproteins.
- Membralin coordinates ER quality control with innate immunity, offering a novel target for antiviral strategies.
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