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O-GlcNAcylation and chaperonin CCT5 protect OTX2 from aggregation in medulloblastoma cellsO-GlcNAcylation andanalysis of OTX2 O-GlcNac sites and dependent interactions

ABSTRACT: In this study, we demonstrated that OTX2 was transcriptionally and post-transcriptionally regulated by O-GlcNAcylation. We describe the modes of degradation of this essential homeobox protein involving both the proteasome and macroautophagy. While the proteasome remains the canonical degradation pathway, we demonstrated that OTX2 forms oligomers and/or aggregates that are resistant to proteasomal degradation and require macroautophagy. Furthermore, elevated cellular concentration of OTX2 promoted aggregation, OTX2 could either interact with the chaperonin CCT5 or be O-GlcNAcylated at the key residues (S1135/S136/T137) to prevent its oligomerization, suggesting a protective role of O-GlcNAcylation in OTX2 turnover.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Stephanie Olivier-Van Stichelen

LAB HEAD: Stephanie Olivier-Van Stichelen

PROVIDER: PXD040353 | Pride | 2024-01-22

REPOSITORIES: Pride

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O-GlcNAcylation regulates OTX2's proteostasis.

Wulff-Fuentes Eugenia E Boakye Jeffrey J Kroenke Kaeley K Berendt Rex R RR Martinez-Morant Carla C Pereckas Michaela M Hanover John A JA Olivier-Van Stichelen Stephanie S

iScience 20231012 11

O-GlcNAcylation is a key post-translational modification, playing a vital role in cell signaling during development, especially in the brain. In this study, we investigated the role of O-GlcNAcylation in regulating the homeobox protein OTX2, which contributes to various brain disorders, such as combined pituitary hormone deficiency, retinopathy, and medulloblastoma. Our research demonstrated that, under normal physiological conditions, the proteasome plays a pivotal role in breakin ...[more]

PMID: 38026167

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