New Insights Into the Biology of Protein O-GlcNAcylation: Approaches and Observations

Abstract

O-GlcNAcylation is a protein posttranslational modification that results in the addition of O-GlcNAc to Ser/Thr residues. Since its discovery in the 1980s, it has been shown to play an important role in a broad range of cellular functions by modifying nuclear, cytosolic, and mitochondrial proteins. The addition of O-GlcNAc is catalyzed by O-GlcNAc transferase (OGT), and its removal is catalyzed by O-GlcNAcase (OGA). Levels of protein O-GlcNAcylation change in response to nutrient availability and metabolic, oxidative, and proteotoxic stress. OGT and OGA levels, activity, and target engagement are also regulated. Together, this results in adaptive and, on occasions, detrimental responses that affect cellular function and survival, which impact a broad range of pathologies and aging. Over the past several decades, approaches and tools to aid the investigation of the regulation and consequences of protein O-GlcNAcylation have been developed and enhanced. This review is divided into two sections: 1) We will first focus on current standard and advanced technical approaches for assessing enzymatic activities of OGT and OGT, assessing the global and specific protein O-GlcNAcylation and 2) we will summarize in vivo findings of functional consequences of changing protein O-GlcNAcylation, using genetic and pharmacological approaches.

Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis

“…Targeting integrin/FAK signaling is a potential strategy to treat fibrotic diseases including NASH [ 50 ]. Increased protein O -GlcNAcylation blocks insulin signaling and promotes lipogenesis [ 39 , 51 ]. IP6K1 inhibition may ameliorate metabolic dysfunction and NAFLD/NASH by altering these pathways.…”

“…Protein O -GlcNAcylation has been shown to differentially influence hepatic metabolism and fibrosis [ 39 , 51 ]. Heterozygous OGA- deleted mice (homozygous OGA -KO mice do not survive) develop metabolic dysfunction.…”

Role and therapeutic implications of protein glycosylation in neuroinflammation

“…In terms of O-GlcNAcylation, this modification differs from N-and O-linked glycans since it is mainly present in cytosolic or nuclear proteins. Its function remains incompletely understood due to the lack of integrated studies of how O-GlcNAcomes are modulated and influence the other '-omic' components of healthy and/or pathological states [49]. Its importance in brain injuries is highlighted in TBI, in which an initial increase in this modification was seen (first 4 h post injury), whereas a decrease occurred after 12 h in a preclinical model.…”

Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease

“…Downstream of glucose phosphorylation by hexokinase, the hexoamine biosynthesis pathway (HBP) generates O -GlcNAc to enable post-translational modification of proteins on Ser/Thr residues 110 . This post-translational modification is sensitive to nutrient availability and cellular stress 26 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 .…”

“…Downstream of glucose phosphorylation by hexokinase, the hexoamine biosynthesis pathway (HBP) generates O -GlcNAc to enable post-translational modification of proteins on Ser/Thr residues 110 . This post-translational modification is sensitive to nutrient availability and cellular stress 26 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 . It has been observed that pharmacological inhibition of the enzyme that removes the O -GlcNAc from proteins resulted in more preserved tau O -GlcNAcylation, and decreased tau phosphorylation and aggregation 22 , 118 , 119 , 120 , 121 .…”