Cell Stress and Chaperones

, Volume 18, Issue 5, pp 535–558

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

  • Jennifer A. Groves
  • Albert Lee
  • Gokben Yildirir
  • Natasha E. Zachara
Mini Review

DOI: 10.1007/s12192-013-0426-y

Cite this article as:
Groves, J.A., Lee, A., Yildirir, G. et al. Cell Stress and Chaperones (2013) 18: 535. doi:10.1007/s12192-013-0426-y

Abstract

O-linked N-acetyl-β-d-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (O-GlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced O-GlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer’s and Parkinson’s diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.

Keywords

O-GlcNAcStressSignal transductionO-GlcNAc transferaseO-GlcNAcasePost-translational modification

Abbreviations

4-OHT

4-Hydroxytamoxifen

AD

Alzheimer’s disease

APP

Amyloid β precursor protein

Amyloid β

Bcl-2

B-cell lymphoma 2

BEMAD

Beta elimination and Michael addition

CaMK

Ca2+/calmodulin-dependent kinase

CCE

Capacitative Ca2+ entry

CID

Collision-induced dissociation

DON

6-Diazo-5-oxo-L-norleucine

Emeg32

Glucosamine-6-phosphate acetyltransferase

eNOS

Endothelial nitric oxide synthase

ESI

Electrospray ionization

ETD

Electron transfer dissociation

FDGlcNAc

Fluorescein di-N-acetyl-β-d-glucosaminide

Foxo

Forkhead box

FRET

Förster resonance energy transfer

GalNAz

N-azidoacetylgalactosamine

GalT1

UDP-Gal/GlcNAcβ-1,4-galactosyltransferase

GE

Gel electrophoresis

GFAT

Glutamine/fructose-6-phosphate amidotransferase

GlcNAz

N-azidoacetylglucosamine

GSK3β

Glycogen synthase kinase 3β

HAT

Histone acetyltransferase

HBP

Hexosamine biosynthetic pathway

Hex

Hexosaminidase

HK

Hexokinase

HSC

Heat shock cognate

HSF

Heat shock factor

HSP

Heat shock protein

I/R

Ischemia–reperfusion

IKKβ

Inhibitor of NFκB kinase

IL

Interleukin

IP3

Inositol (3,4,5)-trisphosphate

IRS-1

Insulin receptor substrate 1

K18

Cytokeratin 18

LC

Liquid chromatography

LWAC

Lectin weak affinity chromatography

MALDI

Matrix-assisted laser desorption ionization

MAP3K7

Mitogen-activated protein kinase kinase kinase 7

MAPK

Mitogen-activated protein kinase

Mgea5

Meningioma-expressed antigen 5

mOGT

Mitochondrial OGT

mPTP

Mitochondrial permeability transition pore

MS

Mass spectrometry

MS/MS

Tandem mass spectrometry

nCl

Negative chemical ionization

ncOGT

Nuclear/cytoplasmic OGT

NFκB

Nuclear factor κB

NO

Nitric oxide

O-GlcNAc

O-linked N-acetyl-β-d-glucosamine

O-GlcNAcase (OGA)

N-acetyl-β-glucosaminidase

O-GlcNAcylated

O-GlcNAc-modified

OGT (O-GlcNAc transferase)

UDP-N-acetylglucosamine/peptide N-acetylglucosaminyl-transferase

PD

Parkinson’s disease

PGC1α

Peroxisome proliferator-activated receptor gamma coactivator 1-α

Pgm3

N-acetylglucosamine-phosphate mutase

PI3K

Phosphoinositide 3-kinase

PIP3

Phosphatidylinositol (3,4,5)-trisphosphate

PNGase

F Peptide N-glycosidase F

pNP-β-GlcNAc

p-Nitrophenol-N-acetyl-β-d-glucosamine

PRMT4/Carm1

Protein arginine methyltransferase 4

PTM

Post-translational modification

PUGNAc

O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate

QTOF

Quadrupole time-of-flight

Rb

Retinoblastoma protein

ROS

Reactive oxygen species

RT-PCR

Real-time polymerase chain reaction

SILAC

Stable isotope labeling with amino acids in cell culture

STZ

Streptozotocin

sWGA

Succinylated WGA

TAB1

TAK1-binding protein

TAD

Transactivation domain

TAK1

TGF-β-activated kinase I

TGF

Transforming growth factor

TMG

(thiamet-G) 2-Ethylamino-3aR, 6S, 7R, 7aR-tetrahydro-5R-hydroxymethyl-5H-pyrano[3, 2-d]thiazole-6,7-diol

TNF-α

Tumor necrosis factor-α

TRP

Tetratricopeptide

Uap1

UDP-GlcNAc pyrophosphorylase

UDP

Uridine diphosphate

UL32

Human cytomegalovirus tegument basic phosphoprotein

VDAC

Voltage-dependent anion channel

WGA

Wheat germ agglutinin

Copyright information

© Cell Stress Society International 2013

Authors and Affiliations

  • Jennifer A. Groves
    • 1
  • Albert Lee
    • 1
  • Gokben Yildirir
    • 1
  • Natasha E. Zachara
    • 1
  1. 1.The Department of Biological ChemistryThe Johns Hopkins University School of MedicineBaltimoreUSA