J Clin Biochem Nutr. 2010 Jan;46(1):14-9. doi: 10.3164/jcbn.SR09-70. Epub 2009 Dec 29.

A new paradigm for antimicrobial host defense mediated by a nitrated cyclic nucleotide.

Journal of clinical biochemistry and nutrition

Tatsuya Okamoto, Shahzada Khan, Kohta Oyama, Shigemoto Fujii, Tomohiro Sawa, Takaaki Akaike

PMID: 20104260 PMCID: PMC2803128 DOI: 10.3164/jcbn.SR09-70

Abstract

Nitric oxide (NO), produced by inducible NO synthase (iNOS) during infection, plays a crucial role in host defense mechanisms. Salmonella typhimurium infection in mice is associated with excessive production of NO from iNOS as a host defense response. An important cytoprotective and antimicrobial function of NO is mediated by induction of heme oxygenase (HO)-1. The signaling mechanism of NO-dependent HO-1 induction has remained unclear, however. We recently discovered a nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which is formed via guanine nitration with NO and reactive oxygen species. iNOS-dependent 8-nitro-cGMP formation and HO-1 induction were identified in Salmonella-infected mice. Extensive apoptosis observed with iNOS-deficient macrophages infected with Salmonella was remarkably suppressed via HO-1 induced by 8-nitro-cGMP formed in cells. This cytoprotective signaling appears to be mediated by the reaction of 8-nitro-cGMP with protein sulfhydryls to generate a novel post-translational modification named protein S-guanylation. We also found that 8-nitro-cGMP specifically S-guanylates Keap1, a negative regulator of transcription factor Nrf2, which in turn up-regulates transcription of HO-1. Here, we discuss the unique mechanism of NO-mediated host defense that operates via formation of a novel signaling molecule - 8-nitro-cGMP - during microbial infections.

Keywords: 8-nitro-cGMP; heme oxygenase-1; host defense; nitric oxide; protein S-guanylation

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