Nippon Saikingaku Zasshi

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Nitric oxide (NO) and reactive oxygen species (ROS) produced during infection are involved critically in host defense mechanisms. It is quite important to physiologically regulate ROS, such as superoxide, and NO. These reactive species produced in excess may cause oxidative damage of biological molecules. An important cytoprotective and antimicrobial function of NO and ROS is mediated by induction of heme oxygenase (HO)-1. The signaling mechanism of this HO-1 induction has remained unclear, however. We discovered in 2007 a unique second messenger, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), that mediates electrophilic signal transduction during oxidative stress and other cellular redox signaling in general. 8-Nitro-cGMP is formed via guanine nitration with NO and ROS, and in fact, NO-dependent 8-nitro-cGMP formation and HO-1 induction were identified in Salmonella-infected mice. HO-1 induction was regulated solely by 8-nitro-cGMP formed in cells, and more important, its potent anti-apoptotic function was evident in such a Salmonella infection. 8-Nitro-cGMP has a potent cytoprotective function, of which signaling appears to be mediated via protein sulfhydryls to generate a post-translational modification called protein S-guanylation. 8-Nitro-cGMP specifically S-guanylates Keap1, a negative regulator of transcription factor Nrf2, which in turn up-regulates transcription of HO-1. Our recent study revealed that the autophagy might be involved in the 8-nitro-cGMP-dependent antimicrobial effect. The 8-nitro-cGMP signaling was also found to be regulated by reactive sulfur species that have superior antioxidant activity and unique signaling function. This review will discuss a new paradigm of the host defense that operates via formation of a unique cell signaling molecule, 8-nitro-cGMP, during microbial infections.

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The bacterial flagellum is a filamentous organelle that propels the bacterial cell body in liquid media. For construction of the bacterial flagellum beyond the cytoplasmic membrane, flagellar component proteins are transported by its specific protein export apparatus from the cytoplasm to the distal end of the growing flagellar structure. The flagellar export apparatus consists of a transmembrane export gate complex and a cytoplasmic ATPase ring complex. Flagellar substrate-specific chaperones bind to their cognate substrates in the cytoplasm and escort the substrates to the docking platform of the export gate. The export apparatus utilizes ATP and proton motive force across the cytoplasmic membrane as the energy sources to drive protein export and coordinates protein export with assembly by ordered export of substrates to parallel with their order of assembly. In this review, we summarize our current understanding of the structure and function of the flagellar protein export system in Salmonella enterica serovar Typhimurium.

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