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

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Cell Stress and Chaperones Aims and scope

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.

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Abbreviations

4-OHT:

4-Hydroxytamoxifen

AD:

Alzheimer’s disease

APP:

Amyloid β precursor protein

Aβ:

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

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Acknowledgments

We apologize to our colleagues whose work was not cited in this review due to theme or space restrictions. Natasha E. Zachara, Ph.D., is funded by grants from the American Heart Association (SD0930162N) and the National Heart, Lung, and Blood Institute (R21-HL-108003 and 1P01-HL-107153). Albert Lee, Ph.D., receives funding as a GCF fellow from the National Heart, Lung and Blood Institute PEG Program (P01-HL-107153).

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There are no conflicts of interest, financial or otherwise, declared by the authors of this paper.

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  1. The Department of Biological Chemistry, The Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD, 21205-2185, USA

    Jennifer A. Groves, Albert Lee, Gokben Yildirir & Natasha E. Zachara

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  1. Jennifer A. Groves
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  2. Albert Lee
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Correspondence to Natasha E. Zachara.

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Jennifer A. Groves and Albert Lee contributed equally to this paper.

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Groves, J.A., Lee, A., Yildirir, G. et al. Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis. Cell Stress and Chaperones 18, 535–558 (2013). https://doi.org/10.1007/s12192-013-0426-y

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