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bioRxiv · 10.1101/2025.01.15.633243

ER-associated degradation relying on protein O-mannosylation

Lemus, L.·Meyer, H.·Rodriguez, A. I.·Schuldiner, M.·Goder, V.
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Abstract

Protein quality control in the secretory pathway, whose dysfunction is linked to various human diseases, begins in the endoplasmic reticulum (ER) and involves ER-associated degradation (ERAD) of terminally misfolded species. We have addressed the roles of protein O-mannosylation in ERAD using complementary genome-wide screens in yeast. Our findings reveal that protein O-mannosylation by the conserved ER-resident O-mannosyltransferase complex Pbn1-Gpi14 generates ERAD cues. This mechanism participates in regulating ERAD of substrates that contain serine-rich regions and provides a fail-safe mechanism for the degradation of non-N-glycosylated misfolded proteins. Our data suggest that the de novo synthesis of ERAD cues through protein O-mannosylation is an essential component of ER quality control.

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Lemus, L., Meyer, H., Rodriguez, A. I., Schuldiner, M., Goder, V.. 2025-01-15. ER-associated degradation relying on protein O-mannosylation. https://doi.org/10.1101/2025.01.15.633243

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