O-GlcNAcylation regulates OTX2's proteostasis

  • iScience. 2023 Oct 12;26(11):108184. doi: 10.1016/j.isci.2023.108184.
Eugenia Wulff-Fuentes  1 ,  Jeffrey Boakye  2 ,  Kaeley Kroenke  1 ,  Rex R Berendt  1 ,  Carla Martinez-Morant  1 ,  Michaela Pereckas  1 ,  John A Hanover  2 ,  Stephanie Olivier-Van Stichelen  1  3
Affiliations
  • 1. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • 2. Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0851, USA.
  • 3. Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
PMID: 38026167 DOI: 10.1016/j.isci.2023.108184
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.

Keywords
Biochemistry; Cancer; Cell biology; Proteomics.
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