Regulation of Protein Degradation by O-GlcNAcylation: Crosstalk with Ubiquitination

Abstract

The post-translational modification of intracellular proteins by O-linked N-acetylglucosamine (O-GlcNAc) regulates essential cellular processes such as signal transduction, transcription, translation, and protein degradation. Misfolded, damaged, and unwanted proteins are tagged with a chain of ubiquitin moieties for degradation by the proteasome, which is critical for cellular homeostasis. In this review, we summarize the current knowledge of the interplay between O-GlcNAcylation and ubiquitination in the control of protein degradation. Understanding the mechanisms of action of O-GlcNAcylation in the ubiquitin-proteosome system shall facilitate the development of therapeutics for human diseases such as cancer, metabolic syndrome, and neurodegenerative diseases. Molecular & Cellular

Functional Implications of O-GlcNAcylation-dependent Phosphorylation at a Proximal Site on Keratin 18

“…The K18 phosphorylation-specific antibodies K18-Ser(P) 33 (clone IB4) and anti K18-Ser(P) 52 (clone 3055) were a gift from Prof. Bishr Omary (Michigan Medical School). Cell culture reagents were obtained from Invitrogen.…”

“…1A. The expression of the YFP-tagged K18 transgene in these stable 29 , gSer 30 , and gSer 48 ) and phosphorylation sites (Ser(P) 33 and Ser(P) 52 ) used to generate stable HHL17 lines. B and D, similar numbers of cultured cells were treated for 2 h either with DMSO vehicle control (VC) or OA to extract the soluble and pellet fraction or total cell lysate (TCL) in identical volumes.…”

“…3B), suggesting co-existence of these two modifications on K8 and K18. We further aimed to investigate the relationship/cross-talk between these two modifications on K18 by assessing the levels of site-specific phosphorylation (Ser(P) 33 and Ser(P) 52 ) on various O-GlcNAc mutants of K18. The site-specific K18-Ser(P) 33 and K18-Ser(P) 52 phosphoantibodies have been reported previously (5,40).…”

“…We further aimed to investigate the relationship/cross-talk between these two modifications on K18 by assessing the levels of site-specific phosphorylation (Ser(P) 33 and Ser(P) 52 ) on various O-GlcNAc mutants of K18. The site-specific K18-Ser(P) 33 and K18-Ser(P) 52 phosphoantibodies have been reported previously (5,40). The specificity of K18-Ser 33 phosphoantibody was further confirmed using cells expressing phosphorylation mutants of K18 (K18-S33A and S52A) (data not shown).…”

“…Although O-GlcNAcylation (gSer 29 , 5 gSer 30 , and gSer 48 ) (39) and phosphorylation (Ser(P) 33 and Ser(P) 52 ) (5,40) occur at proximal sites on keratin 18, their mutual interplay in regulating its functional properties is largely unexplored. In our previous report, we showed that total O-GlcNAcylation on keratins 8/18 can regulate solubility, filament organization, and stability (17).…”