OGT controls mammalian cell viability by regulating the proteasome/mTOR/ mitochondrial axis

BioRxiv : the Preprint Server for Biology
X. LiAnjana Rao

Abstract

O-GlcNAc transferase (OGT) is an essential X-chromosome-encoded enzyme that catalyzes the addition of N-acetylglucosamine (GlcNAc) to the hydroxyl groups of serine and threonine residues on many nuclear and cytosolic proteins. This posttranslational modification is reversible and is actively removed by the O-GlcNAcase OGA. It was shown more than two decades ago that OGT is essential for mammalian cell viability, but the underlying mechanisms are still enigmatic. Given the close association between OGT and human diseases, such as cancer, diabetes and cardiovascular disease, identification of the mechanisms by which OGT controls cell viability will facilitate the development of therapeutic strategies to manipulate OGT activity. Here, we employ a genome-wide CRISPR-Cas9 viability screen in mouse embryonic stem cells (mESCs) with inducible Ogt deletion to show that the block in cell viability induced by Ogt-deficiency stems from a deleterious increase in mitochondrial oxidative phosphorylation (OXPHOS). Mechanistically, we demonstrate that OGT safeguards mTOR (mechanistic target of rapamycin) activity to maintain mitochondrial fitness through modulation of proteasome activity and intracellular amino acid homeostasis. In the absence...Continue Reading

Methods Mentioned

BETA
GTPase
nucleotide exchange
flow cytometry
pull down

Software Mentioned

GSEA
PinAPL
Metascape
Metascape Complex Detection
Py

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