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O-GlcNAcylation regulates OTX2's proteostasis. iScience 2023 Nov 17;26(11):108184

Date

11/29/2023

Pubmed ID

38026167

Pubmed Central ID

PMC10661118

DOI

10.1016/j.isci.2023.108184

Scopus ID

2-s2.0-85175489896 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

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 breaking down endogenous OTX2. However, when the levels of OTX2 rise, it forms oligomers and/or aggregates that require macroautophagy for clearance. Intriguingly, we demonstrated that O-GlcNAcylation enhances the solubility of OTX2, thereby limiting the formation of these aggregates. Additionally, we unveiled an interaction between OTX2 and the chaperone protein CCT5 at the O-GlcNAc sites, suggesting a potential collaborative role in preventing OTX2 aggregation. Finally, our study demonstrated that while OTX2 physiologically promotes cell proliferation, an O-GlcNAc-depleted OTX2 is detrimental to cancer cells.

Author List

Wulff-Fuentes E, Boakye J, Kroenke K, Berendt RR, Martinez-Morant C, Pereckas M, Hanover JA, Olivier-Van Stichelen S

Author

Stephanie Olivier-Van Stichelen PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin