MAN1B1

MAN1B1 encodes a Golgi-localized alpha-1,2-mannosidase (ERManI) that functions in N-glycoprotein quality control and endoplasmic-reticulum-associated degradation (ERAD) (PMID:21763484, PMID:21697506). Endogenous human ERManI resides predominantly in the Golgi rather than the ER, where it is O-glycosylated and generates the mannose-trimmed glycan signal that tags misfolded N-glycoproteins for proteasomal degradation; redistributing it toward the ER accelerates glycan trimming of misfolded alpha1-antitrypsin but not substrate degradation, placing the tagging step in the Golgi (PMID:21697506). MAN1B1 acts through two mechanistically distinct routes: a conventional catalysis-dependent system requiring an intact luminal active site to accelerate degradation of misfolded alpha1-antitrypsin variants NHK and ATZ, and an unconventional catalysis-independent gatekeeper function in which an extended N-terminal cytoplasmic tail and a conserved luminal stem decapeptide route misfolded substrates for degradation without glycan trimming (PMID:24627495, PMID:32958677). Beyond host quality control, MAN1B1 is recruited by the ER-phagy receptor Membralin into a Membralin-MAN1B1-VCP complex that selectively directs densely glycosylated viral envelope glycoproteins to lysosomal degradation via a ubiquitin-independent, LC3-dependent pathway, and its loss enhances pseudoviral infectivity (PMID:41324484); consistent with a direct antiviral role, ERManI physically interacts with and is required for ERAD of HIV-1 envelope glycoprotein (PMID:26205822). MAN1B1 protein stability is set by ERK-dependent control of its interaction with the E3 ubiquitin ligase HRD1, and elevated MAN1B1 promotes CD47 glycosylation and tumor immune evasion (PMID:40493414). Loss-of-function mutations at conserved catalytic residues cause altered Golgi morphology and accumulation of hybrid-type N-glycans in patient cells, defining a congenital disorder of glycosylation (PMID:21763484, PMID:24348268).

1. 2011 Medium

   Establishing that MAN1B1 is an alpha-1,2-mannosidase whose catalytic activity is required for normal function answered whether the gene's disease relevance is enzymatic.

   Evidence Sanger sequencing of patients plus kinetic and expression assays of missense mutants in mammalian cells

   PMID:21763484

   Open questions at the time

   • Did not localize the enzyme or define which substrates it acts on
   • Does not separate loss of catalysis from loss of protein stability as the disease driver
2. 2011 High

   Localizing endogenous ERManI to the Golgi rather than the ER reassigned where the ERAD glycan-tagging signal is generated, overturning the assumption of ER residence.

   Evidence Subcellular fractionation, immunofluorescence, O-glycosylation analysis, COPI-motif redistribution, and pulse-chase degradation in human cells

   PMID:21697506

   Open questions at the time

   • Mechanism coupling Golgi trimming to downstream proteasomal delivery not defined
   • Did not address catalysis-independent functions
3. 2013 Medium

   Patient-derived cells linked MAN1B1 loss to altered Golgi morphology and hybrid-type N-glycan accumulation, connecting the enzyme defect to a cellular and glycomic phenotype.

   Evidence Exome sequencing, fibroblast immunofluorescence, and glycan analysis

   PMID:24348268

   Open questions at the time

   • Causality between Golgi dilatation and mannosidase loss not mechanistically resolved
4. 2013 Medium

   Identification of MAN1B1 as a miR-125b target with proliferation/migration/invasion phenotypes raised a quality-control-independent role in hepatocellular carcinoma.

   Evidence 3'UTR reporter, RNAi knockdown, and functional cell assays in hepatoma cells

   PMID:23940818

   Open questions at the time

   • Molecular basis of the cancer phenotype distinct from glycoprotein QC not defined
   • Single cell-type context
5. 2014 High

   Demonstrating that neither catalysis nor the catalytic domain is required for retention/degradation of misfolded NHK revealed a non-enzymatic gatekeeper function localized to a luminal stem decapeptide.

   Evidence Active-site mutagenesis, domain truncations, and ERAD reporter assays

   PMID:24627495

   Open questions at the time

   • Binding partners executing the non-enzymatic routing not identified
   • How the decapeptide selects substrates unknown
6. 2015 High

   Showing ERManI is required for HIV-1 Env ERAD and physically interacts with Env via its catalytic domain extended MAN1B1 function to viral glycoprotein clearance.

   Evidence Ectopic expression, CRISPR knockout, co-IP, domain mapping, and catalytic-site mutagenesis

   PMID:26205822

   Open questions at the time

   • Degradation route (proteasome vs lysosome) for Env not resolved here
   • Relationship to the non-enzymatic pathway unclear
7. 2020 High

   Resolving the functional dichotomy distinguished a luminal catalysis-dependent ERAD system from an N-terminal cytoplasmic-tail-driven catalysis- and glycan-independent system.

   Evidence Knockout HEK293T reconstitution with mutant/truncated constructs, pulse-chase, proteasome inhibition, and substrate N-glycan-site mutagenesis

   PMID:32958677

   Open questions at the time

   • Effectors recruited by the cytoplasmic tail not identified
   • Structural basis for dual mechanism not defined
8. 2025 Medium

   Defining the Membralin-MAN1B1-VCP complex established a ubiquitin-independent, LC3-dependent ERLAD route that selectively degrades densely glycosylated viral fusion glycoproteins.

   Evidence Reciprocal co-IP with domain mapping, MAN1B1 knockout, pseudoviral infectivity, and lysosomal/LC3-LIR functional assays

   PMID:41324484

   Open questions at the time

   • Single lab, newly published
   • How dense glycosylation is sensed mechanistically not resolved
   • Stoichiometry and assembly order of the complex unknown
9. 2025 Medium

   Linking ERK to HRD1-mediated MAN1B1 turnover explained how MAN1B1 levels are set and connected its stabilization to CD47 glycosylation and tumor immune evasion.

   Evidence Western blotting, MAN1B1-HRD1 co-IP, MAN1B1 knockout in vitro and in mice, ERK inhibition, and phagocytosis assays

   PMID:40493414

   Open questions at the time

   • Whether MAN1B1 directly glycosylates CD47 vs acts indirectly not fully resolved
   • Single lab
10. 2025 Medium

    A luminal juxtamembrane helical charge motif was shown to partition ERManI between quality-control vesicles and the Golgi, identifying a sorting determinant for its localization.

    Evidence Charge/helical-register mutagenesis, domain grafting onto an unrelated transmembrane protein, and live-cell localization (preprint)

    PMID:bio_10.1101_2025.11.12.688035

    Open questions at the time

    • Preprint, not yet peer-reviewed
    • Identity of the trafficking machinery reading this motif unknown
    • Functional consequence of QCV vs Golgi residence for ERAD not established

• How the catalytic, non-enzymatic cytoplasmic-tail, ERLAD, and trafficking activities are integrated and coordinated on individual substrates remains unresolved.
• No structural model coupling the dual mechanisms
• Cytoplasmic-tail effectors and ERLAD assembly factors not fully mapped
• Substrate selection rules for each pathway undefined