Truncated N-glycans destabilize POMT1 and POMT2 but do not limit cellular O-mannosylation in HEK293 cells

-type N-glycans and their steady-state protein levels are reduced by more than half, despite unchanged transcript levels. In vitro, reduced POMT abundance resulted in a proportional decrease in mannosyltransferase activity. However, O-mannosylation in cells remained unaffected: α-dystroglycan displayed normal matriglycan extension and a highly O-mannosylated KIAA1549 reporter showed unaltered site occupancy and core structures. These data indicate that POMT activity operates with substantial catalytic reserve under basal conditions, sufficient to tolerate significant reduction in enzyme levels without impairing substrate modification. Our work identifies ALG3-mediated N-glycan maturation as a determinant of POMT stability, highlights buffering capacity that preserves substrate O-mannosylation despite reduced enzyme abundance, and provides a mechanistic framework for how N-glycosylation defects could modulate POMT-dependent glycosylation in disease.

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Publication Details

Journal
Molecular Genetics and Metabolism
Published
2026-04-06
DOI
https://doi.org/10.1016/j.ymgme.2026.110115
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Truncated N-glycans destabilize POMT1 and POMT2 but do not limit cellular O-mannosylation in HEK293 cells

Marcus Hoffmann, Sabine Strahl, Sergey Y. Vakhrushev, Andreas Harst et al.
Molecular Genetics and Metabolism
Glycosylation and Glycoproteins Research
article

Truncated N-glycans destabilize POMT1 and POMT2 but do not limit cellular O-mannosylation in HEK293 cells

Marcus Hoffmann, Sabine Strahl, Sergey Y. Vakhrushev, Andreas Harst, Erdmann Rapp, Thomas Ruppert, Robert Burock, Andriana Konstantinidi, Christina Hölscher, Ivan Andújar Martínez, Daniel Sturm, Adnan Halim, Shahidul Alam, Christian Thiel
article en

Abstract

-type N-glycans and their steady-state protein levels are reduced by more than half, despite unchanged transcript levels. In vitro, reduced POMT abundance resulted in a proportional decrease in mannosyltransferase activity. However, O-mannosylation in cells remained unaffected: α-dystroglycan displayed normal matriglycan extension and a highly O-mannosylated KIAA1549 reporter showed unaltered site occupancy and core structures. These data indicate that POMT activity operates with substantial catalytic reserve under basal conditions, sufficient to tolerate significant reduction in enzyme levels without impairing substrate modification. Our work identifies ALG3-mediated N-glycan maturation as a determinant of POMT stability, highlights buffering capacity that preserves substrate O-mannosylation despite reduced enzyme abundance, and provides a mechanistic framework for how N-glycosylation defects could modulate POMT-dependent glycosylation in disease.

Molecular Genetics and MetabolismVol. 148(2)
University of Copenhagen (DK), Heidelberg University (DE), University Hospital Heidelberg (DE), Max Planck Institute for Dynamics of Complex Technical Systems (DE), European Molecular Biology Laboratory (DE), Heidelberg University (US)
Villum Fonden, Deutsche Forschungsgemeinschaft, Danmarks Grundforskningsfond, Carlsbergfondet, Novo Nordisk Fonden
Openalex Percentile: Top 25%
Glycosylation and Glycoproteins Research
DOIOpen Access PDFOpenAlex
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