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Sulfhydryl-mediated redox signaling in inflammation: role in neurodegenerative diseases

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Abstract

Posttranslational modifications of cysteine sulfhydryl (–SH) moieties, e.g., S-nitrosylation, S-glutathionylation, or S-sulfuration, play an important role in cellular response to oxidative stress. Reversible cysteine modifications alter protein function and can play a critical role in redox signal transduction. Perturbation of sulfhydryl homeostasis is a hallmark of many diseases, including neurodegenerative disorders. Besides direct oxidative stress within the neurons, inflammation of the central nervous system as well as the periphery is implicated also in the development and progression of neurodegeneration. Therefore, perturbation of redox regulation of key inflammatory mediators is an important component of neurodegenerative diseases. Many proteins involved in inflammation have been shown to undergo S-nitrosylation (–SNO) and/or S-glutathionylation (–SSG) with functional consequences. The mechanistic and functional relationships between these two modifications have yet to be thoroughly investigated. While protein–SNO intermediates in some cases may signal independently of protein–SSG intermediates, the relatively unstable nature of protein–SNO derivatives in the presence of GSH suggests that protein–SNO formation in many cases may serve as a precursor for protein–SSG modifications. In this review, we describe the cysteine modifications of specific inflammation-mediating proteins and their relationship to inflammatory responses such as cytokine and chemokine production. In particular, we consider evidence for sequential protein–SNO → protein–SSG modifications of these proteins. We conclude that cysteine modifications of critical regulatory proteins are likely to play a central role in the onset and progression of neuroinflammatory diseases and thus should be studied thoroughly in this context.

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Abbreviations

ACT:

α1-Antichymotrypsin

AD:

Alzheimer’s disease

Akt/PKB:

Protein kinase B

ALS:

Amyotrophic lateral sclerosis

APP:

Amyloid precursor protein

Aβ:

Amyloid-beta

BioGEE:

Biotinylated glutathione ethyl ester

Biotin-HPDP:

N-[(6-biotinamido)hexyl]-3′-(2′-pyridyldithio) propionamide

BMDM:

Bone marrow derived macrophages

CD4:

Cluster of differentiation 4

CNS:

Central nervous system

COX2:

Cyclooxygenase 2

CSE:

Cystathionine γ-lyase

CSF:

Cerebrospinal fluid

CXCR3/4:

Chemokine receptor 3/4

Cys-SNO:

S-nitrosocysteine

DAMPs:

Damage-associated molecular patterns

DTT:

Dithiothreitol

EAE:

Experimental autoimmune encephalomyelitis

eNOS:

Endothelial nitric oxide synthase

ERK1/2:

Extracellular-signal-regulated kinase 1/2

GCL:

Glutamate cysteine ligase

GGCS:

Gamma-glutamylcysteine synthetase

Grx:

Glutaredoxin

Grx1:

Glutaredoxin-1

GS· :

Glutathione radical

GSH:

Glutathione

GSNO:

S-Nitrosoglutathione

GSSG:

Glutathione disulfide

GST:

Glutathione-S-transferase

GSTπ:

Glutathione S-transferase pi

H2S:

Hydrogen sulfide

HD:

Huntington’s disease

HMGB1:

High-mobility group protein B1

HO-1:

Heme oxygenase 1

IAM:

Iodoacetamide

Iba:

Ionized calcium-binding adaptor molecule 1

ICE:

Interleukin-1 converting enzyme

IKKα:

Inhibitor of nuclear factor kappa B kinase subunit alpha

IKKβ:

Inhibitor of nuclear factor kappa B kinase subunit beta

IL-1R:

Interleukin 1 receptor

IL-1β:

Interleukin 1 beta

IL-6:

Interleukin 6

INFγ:

Interferon gamma

iNOS:

Inducible nitric oxide synthase

IRAK:

Interleukin-1 receptor-associated kinase

IRF3:

Interferon regulatory factor 3

IκBα:

Inhibitory kappa B alpha

IκBα:

Nuclear factor of kappa-light polypeptide gene enhancer in B cells inhibitor, alpha

JNK:

c-Jun N-terminal kinase

LPS:

Lipopolysaccharide

LRRK2:

Leucine-rich repeat kinase 2

LTβR:

Lymphotoxin-beta receptor

MMTS:

S-Methyl methanethiosulfonate

MND:

Motor neuron disease

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS:

Multiple sclerosis

MyD88:

Myeloid differentiation primary response gene (88)

NADP+/H:

Nicotinamide adenine dinucleotide phosphate (oxidized/reduced)

NFκB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NFκB2/p100:

Nuclear factor NF-kappa B p100 subunit

NLRP3:

NACHT, LRR and PYD domains-containing protein 3

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

NSAID:

Non-steroid anti-inflammatory drug

PAMPs:

Pathogen-associated molecular patterns

PD:

Parkinson’s disease

PKB:

Protein kinase B

PPARγ:

Peroxisome proliferator-activated receptor gamma

Pro-SH:

Reduced protein thiol

Pro-SNO:

S-nitrosylated protein

Pro-SO2H:

Protein sulfinic acid

Pro-SO3H:

Protein sulfonic acid

Pro-SOH:

Protein sulfenic acid

Pro-SSG:

Glutathionylated protein

Pro-SSH:

Sulfhydrated protein

PS1:

Presenilin-1

PTEN:

Phosphatase and tensin analog deleted from chromosome 10

Rac1:

Ras-related C3 botulinum toxin substrate 1

RING:

Really interesting new gene

ROS:

Reactive oxygen species

RTK:

Receptor tyrosine kinase

S100:

Soluble in 100 % ammonium sulfate at neutral pH

S100A8:

S100 calcium-binding protein A8

S100A9:

S100 calcium-binding protein A9

SNAP:

S-nitroso-N-acetylpenicillamine

SOD:

Superoxide dismutase

solTNF-α:

Soluble TNF-α

STAT3:

Signal transducer and activator of transcription 3

TAB:

TAK1-binding protein

TAK1:

TGF (transforming growth factor) beta-activated kinase 1

TLR:

Toll-like receptor

tmTNF-α:

Transmembrane TNF-α

TNF-α:

Tumor necrosis factor alpha

TNFR:

Tumor necrosis factor receptor

TR:

Thioredoxin reductase

TRAF6:

Tumor necrosis factor receptor-associated factor 6

Trx:

Thioredoxin

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Acknowledgments

We thank Clinton J. Miller, Michael E. Maguire, and George Dubyak for critical reading of manuscript prior to submission. This work was supported in part by Department of Veterans Affairs (merit review Grant BX000290 to J.J.M.).

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  1. Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106-4965, USA

    Olga Gorelenkova Miller & John J. Mieyal

  2. Louis Stokes Cleveland Veterans Administration Medical Research Center, Cleveland, OH, 44106, USA

    John J. Mieyal

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Gorelenkova Miller, O., Mieyal, J.J. Sulfhydryl-mediated redox signaling in inflammation: role in neurodegenerative diseases. Arch Toxicol 89, 1439–1467 (2015). https://doi.org/10.1007/s00204-015-1496-7

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