MOGS

MOGS encodes the ER-resident alpha-glucosidase I that catalyzes the first committed step of N-glycan processing, removing the terminal alpha-1,2-linked glucose from the Glc3Man9GlcNAc2 oligosaccharide on newly synthesized glycoproteins, an activity established through its yeast ortholog CWH41/DER7 and conserved from bacteria to humans (PMID:9363442, PMID:15450188, PMID:40674822). The enzyme is a type II integral ER membrane glycoprotein whose catalytic domain is trypsin-resistant and active in soluble form (PMID:8576053, PMID:14680956). Loss of glucosidase I activity causes accumulation of fully triglucosylated glycoproteins, and this accumulation — rather than disruption of calnexin cycling or proteasomal degradation — is the primary toxic event that distorts the ER and cell wall and underlies the human MOGS-CDG disorder, for which a complementation assay quantifies the residual activity of disease-related mutants (PMID:30389790, PMID:40674822). Glucosidase I activity is required for ERAD of misfolded glycoproteins and for limiting ER stress (PMID:15450188, PMID:30389790). Beyond its catalytic role, MOGS modulates ER stress and lipid homeostasis: it is bound and destabilized by p32 through lysosomal degradation, and elevated MOGS suppresses fatty-acid-induced ER stress and lipogenic gene activation (PMID:29465311). In colorectal cancer cells MOGS binds GRP78 and recruits the deubiquitinase USP10 to stabilize GRP78, reducing ER-stress-mediated apoptosis and promoting tumor growth (PMID:39267084). Its N-glycan processing function also supports proper glycoprotein maturation and modulates cell-surface sialic acid abundance relevant to influenza A virus infection.

1. 1996 High

   Established the molecular identity of the gene as the ER alpha-glucosidase I, answering which enzyme initiates trimming of the triglucosylated N-glycan precursor.

   Evidence In vitro enzymatic assay with synthetic trisaccharide and in vivo [3H]mannose labeling of N-glycans in yeast CWH41 null mutants

   PMID:9363442

   Open questions at the time

   • Does not resolve the structural basis of substrate recognition
   • Human enzyme not directly assayed in this study
2. 1996 High

   Defined the enzyme as a type II ER integral membrane glycoprotein and linked it genetically to cell wall beta-1,6-glucan assembly, situating it within glycan-dependent cell envelope biology.

   Evidence Gene disruption, beta-1,6-glucan quantification, and synthetic lethality epistasis with kre6 and kre1 in yeast

   PMID:8576053

   Open questions at the time

   • Connection between glucosidase activity and glucan assembly is genetic, not biochemical
   • Relevance to mammalian cells not addressed
3. 2004 High

   Demonstrated that glucosidase I activity is essential for ERAD and prevention of ER stress, identifying a specific catalytic-residue requirement.

   Evidence Identification of a G725R substitution in yeast DER7 with ERAD and ER stress marker readouts

   PMID:15450188

   Open questions at the time

   • Mechanism linking glycan trimming to ERAD substrate selection not detailed
   • Single mutant residue characterized
4. 2004 Medium

   Showed the catalytic domain is autonomously active and stable, enabling biochemical isolation of the functional enzyme.

   Evidence Purification of soluble enzyme and controlled trypsin digestion with retained activity toward Glc3Man9GlcNAc2

   PMID:14680956

   Open questions at the time

   • No atomic-resolution structure determined
   • Study focused on methodology rather than mechanism
5. 2018 Medium

   Identified MOGS as a regulator of ER-stress-mediated lipid homeostasis, connecting it to p32 and lipogenic control beyond glycan trimming.

   Evidence Co-immunoprecipitation, lysosome inhibitor assays, and MOGS overexpression with ER stress and lipogenic gene readouts

   PMID:29465311

   Open questions at the time

   • Whether the lipid effect requires catalytic activity is not established
   • Single lab; physiological context of p32 regulation unclear
6. 2018 High

   Pinpointed accumulation of triglucosylated glycoproteins as the primary toxic mechanism of glucosidase I loss, excluding alternative explanations relevant to MOGS-CDG.

   Evidence S. pombe knockout with HPLC glycan analysis, electron microscopy, and complementation with human Golgi endomannosidase

   PMID:30389790

   Open questions at the time

   • Molecular target through which the toxic glycan acts is unidentified
   • Human cellular pathology not directly examined
7. 2023 Low

   Proposed MOGS-dependent glycosylation of NOTCH1 as a route to enhanced NOTCH signaling and stemness in cancer.

   Evidence MOGS knockdown/overexpression with NOTCH1 glycosylation and stemness/invasion assays in colorectal cancer cells

   PMID:38187061

   Open questions at the time

   • Direct glycosylation of NOTCH1 by MOGS not reconstituted
   • Abstract-level description, single lab
   • Causal role of glucosidase activity unconfirmed
8. 2022 Medium

   Demonstrated MOGS is required for N-glycan processing that modulates cell-surface sialic acid and supports influenza A virus infection.

   Evidence Genome-wide CRISPR-Cas9 screen in avian cells with functional validation and sialic acid quantification (preprint)

   Open questions at the time

   • Preprint, not peer-reviewed
   • Direct viral glycoprotein substrate effects in human cells not shown
9. 2022 Low

   Linked MOGS to Schwann cell plasticity and fatty acid metabolism, extending its phenotypic reach to neural cells.

   Evidence siRNA knockdown in Schwann cells with proliferation, migration, differentiation, and FASN expression readouts

   PMID:35575968

   Open questions at the time

   • No mechanistic link between glucosidase activity and Schwann cell biology established
   • Single knockdown experiment, single lab
10. 2024 Medium

    Defined a non-canonical role in which MOGS stabilizes GRP78 via USP10 recruitment to suppress apoptosis and promote tumor progression.

    Evidence Co-immunoprecipitation-mass spectrometry, colocalization, and in vitro/in vivo functional assays including xenografts in colorectal cancer

    PMID:39267084

    Open questions at the time

    • USP10 recruitment mechanism relies on CoIP without reconstitution
    • Whether this role requires glucosidase activity is unresolved
11. 2025 Medium

    Confirmed cross-species conservation of glucosidase I activity and provided a functional assay for human MOGS disease mutants.

    Evidence Complementation of CWH41-knockout S. cerevisiae by bacterial and human MOGS with N-glycan profiling

    PMID:40674822

    Open questions at the time

    • Quantitative correlation between residual activity and patient phenotype not established
    • Single lab

• It remains unresolved how the catalytic glucosidase function mechanistically connects to MOGS's reported roles in lipid homeostasis, GRP78 stabilization, and NOTCH signaling, and what direct molecular target mediates triglucosylated-glycoprotein toxicity.
• No structure of human MOGS in the corpus
• Catalytic dependence of non-canonical roles untested
• Direct mediator of glycan toxicity unidentified