Protein cysteine S-guanylation and electrophilic signal transduction by endogenous nitro-nucleotides
Nitric oxide (NO), a gaseous free radical that is synthesized in organisms by nitric oxide synthases, participates in a critical fashion in the regulation of diverse physiological functions such as vascular and neuronal signal transduction, host defense, and cell death regulation. Two major pathways of NO signaling involve production of the second messenger guanosine 3′,5′-cyclic monophosphate (cGMP) and posttranslational modification (PTM) of redox-sensitive cysteine thiols of proteins. We recently clarified the physiological formation of 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP) as the first demonstration, since the discovery of cGMP more than 40 years ago, of a new second messenger derived from cGMP in mammals. 8-Nitro-cGMP is electrophilic and reacts efficiently with sulfhydryls of proteins to produce a novel PTM via cGMP adduction, a process that we named protein S-guanylation. 8-Nitro-cGMP may regulate electrophilic signaling on the basis of its electrophilicity through induction of S-guanylation of redox sensor proteins. Examples include S-guanylation of the redox sensor protein Kelch-like ECH-associated protein 1 (Keap1), which leads to activation of NF-E2-related factor 2 (Nrf2)-dependent expression of antioxidant and cytoprotective genes. This S-guanylation-mediated activation of an antioxidant adaptive response may play an important role in cytoprotection during bacterial infections and oxidative stress. Identification of new redox-sensitive proteins as targets for S-guanylation may help development of novel therapeutics for oxidative stress- and inflammation-related disorders and vascular diseases as well as understanding of cellular protection against oxidative stress.
KeywordsNitric oxide Reactive oxygen species Oxidative stress Posttranslational modification Redox signal ROS signal Electrophilic signal Adaptive response
We thank Judith B. Gandy for her excellent editing of the manuscript. This work was supported in part by Grants-in-Aid for Scientific Research (B, C: Nos. 21390097, 21590312) and on Innovative Areas (Research in a Proposed Area: Nos. 20117001, 20117005) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, by Advanced Education Program for Young Scientists in Integrated Clinical, Basic and Social Medicine, Kumamoto University, and by Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan.
- Baker PR, Lin Y, Schopfer FJ, Woodcock SR, Groeger AL, Batthyany C, Sweeney S, Long MH, Iles KE, Baker LM, Branchaud BP, Chen YE, Freeman BA (2005) Fatty acid transduction of nitric oxide signaling: multiple nitrated unsaturated fatty acid derivatives exist in human blood and urine and serve as endogenous peroxisome proliferator-activated receptor ligands. J Biol Chem 280:42464–42475PubMedCrossRefGoogle Scholar
- Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 99:11908–11913PubMedCrossRefGoogle Scholar
- Saito Y, Taguchi H, Fujii S, Sawa T, Kida E, Kabuto C, Akaike T, Arimoto H (2008) 8-Nitroguanosines as chemical probes of the protein S-guanylation. Chem Commun 5984–5986Google Scholar
- Sawa T, Tatemichi M, Akaike T, Barbin A, Ohshima H (2006) Analysis of urinary 8-nitroguanine, a marker of nitrative nucleic acid damage, by high-performance liquid chromatography-electrochemical detection coupled with immunoaffinity purification: association with cigarette smoking. Free Radic Biol Med 40:711–720PubMedCrossRefGoogle Scholar
- Sawa T, Arimoto H, Akaike T (2010) Chemical conjugation of protein thiols by nitric oxide and electrophiles in regulation of redox signaling. Bioconj Chem (in press)Google Scholar
- Sugiura H, Ichinose M, Tomaki M, Ogawa H, Koarai A, Kitamuro T, Komaki Y, Akita T, Nishino H, Okamoto S, Akaike T, Hattori T (2004) Quantitative assessment of protein-bound tyrosine nitration in airway secretions from patients with inflammatory airway disease. Free Radic Res 38:49–57PubMedCrossRefGoogle Scholar
- Tazawa H, Tatemichi M, Sawa T, Gilibert I, Ma N, Hiraku Y, Donehower LA, Ohgaki H, Kawanishi S, Ohshima H (2007) Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in Trp53 +/− mice. Carcinogenesis 28:191–198PubMedCrossRefGoogle Scholar
- Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW, Talalay P (2004) Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc Natl Acad Sci USA 101:2040–2045PubMedCrossRefGoogle Scholar
- Yamakura F, Matsumoto T, Ikeda K, Taka H, Fujimura T, Murayama K, Watanabe E, Tamaki M, Imai T, Takamori K (2005) Nitrated and oxidized products of a single tryptophan residue in human Cu, Zn-superoxide dismutase treated with either peroxynitrite-carbon dioxide or myeloperoxidase-hydrogen peroxide-nitrite. J Biochem 138:57–69PubMedCrossRefGoogle Scholar
- Yasuhara R, Miyamoto Y, Akaike T, Akuta T, Nakamura M, Takami M, Morimura N, Yasu K, Kamijo R (2005) Interleukin-1β induces death in chondrocyte-like ATDC5 cells through mitochondrial dysfunction and energy depletion in a reactive nitrogen and oxygen species-dependent manner. Biochem J 389:315–323PubMedCrossRefGoogle Scholar
- Yoshitake J, Kato K, Yoshioka D, Sueishi Y, Sawa T, Akaike T, Yoshimura T (2008) Suppression of NO production and 8-nitroguanosine formation by phenol-containing endocrine-disrupting chemicals in LPS-stimulated macrophages: involvement of estrogen receptor-dependent or -independent pathways. Nitric Oxide 18:223–228PubMedCrossRefGoogle Scholar