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

Okamoto T, Khan S, Oyama K, Fujii S, Sawa T, Akaike T - J Clin Biochem Nutr (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

New post-translational modification of proteins and HO-1 induction by 8-nitro-cGMP. (A) 8-Nitro-cGMP, a novel nitrated cyclic nucleotide generated from NO and ROS in cells, possesses an electrophilic property and causes S-guanylation of proteins, i.e., adduction of cGMP to protein sulfhydryls. (B) 8-Nitro-cGMP activates the Nrf2 pathway via S-guanylation of a sensor protein, Keap1, which leads to HO-1 induction.
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Figure 2: New post-translational modification of proteins and HO-1 induction by 8-nitro-cGMP. (A) 8-Nitro-cGMP, a novel nitrated cyclic nucleotide generated from NO and ROS in cells, possesses an electrophilic property and causes S-guanylation of proteins, i.e., adduction of cGMP to protein sulfhydryls. (B) 8-Nitro-cGMP activates the Nrf2 pathway via S-guanylation of a sensor protein, Keap1, which leads to HO-1 induction.

Mentions: During infection, various cytoprotective and antioxidant systems are induced to protect cells and tissues from pathogenic microbes [24–26]. Heme oxygenase (HO)-1 is known as a factor that is rapidly induced during infection and that contributes to the host defense mechanism [27]. HO-1 degrades free heme, used as a substrate, into biliverdin, iron ions, and carbon monoxide (CO). Both biliverdin and iron ions carry out antioxidant activity by means of reduction to bilirubin and production of ferritin, respectively [28, 29]. CO is known to exhibit cytoprotection via suppressing production of inflammatory cytokines and apoptosis [30]. HO-1 is reportedly induced by various stresses and by multiple transcription factors, e.g., heat shock factor 1 (HSF1), nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and nuclear factor-erythroid 2-related factor 2 (Nrf2) (Fig. 2) [27]. Modulators that upregulate these transcription factors include heat shock or intracellular accumulation of abnormal proteins (HSF1), infection or inflammatory responses (NF-κB), abnormal cell growth (AP-1), and electrophiles or oxidants (Nrf2).


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

Okamoto T, Khan S, Oyama K, Fujii S, Sawa T, Akaike T - J Clin Biochem Nutr (2009)

New post-translational modification of proteins and HO-1 induction by 8-nitro-cGMP. (A) 8-Nitro-cGMP, a novel nitrated cyclic nucleotide generated from NO and ROS in cells, possesses an electrophilic property and causes S-guanylation of proteins, i.e., adduction of cGMP to protein sulfhydryls. (B) 8-Nitro-cGMP activates the Nrf2 pathway via S-guanylation of a sensor protein, Keap1, which leads to HO-1 induction.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2803128&req=5

Figure 2: New post-translational modification of proteins and HO-1 induction by 8-nitro-cGMP. (A) 8-Nitro-cGMP, a novel nitrated cyclic nucleotide generated from NO and ROS in cells, possesses an electrophilic property and causes S-guanylation of proteins, i.e., adduction of cGMP to protein sulfhydryls. (B) 8-Nitro-cGMP activates the Nrf2 pathway via S-guanylation of a sensor protein, Keap1, which leads to HO-1 induction.
Mentions: During infection, various cytoprotective and antioxidant systems are induced to protect cells and tissues from pathogenic microbes [24–26]. Heme oxygenase (HO)-1 is known as a factor that is rapidly induced during infection and that contributes to the host defense mechanism [27]. HO-1 degrades free heme, used as a substrate, into biliverdin, iron ions, and carbon monoxide (CO). Both biliverdin and iron ions carry out antioxidant activity by means of reduction to bilirubin and production of ferritin, respectively [28, 29]. CO is known to exhibit cytoprotection via suppressing production of inflammatory cytokines and apoptosis [30]. HO-1 is reportedly induced by various stresses and by multiple transcription factors, e.g., heat shock factor 1 (HSF1), nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and nuclear factor-erythroid 2-related factor 2 (Nrf2) (Fig. 2) [27]. Modulators that upregulate these transcription factors include heat shock or intracellular accumulation of abnormal proteins (HSF1), infection or inflammatory responses (NF-κB), abnormal cell growth (AP-1), and electrophiles or oxidants (Nrf2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

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.

No MeSH data available.


Related in: MedlinePlus