[ODP6F] f. Immune Mechanism, Development of Vaccines

[ODP-179] NADPH oxidases and NO synthases activate super sulfur species conferring anti-microbial host defense

○Tsuyoshi Takata¹, Tomoaki Ida¹, Tetsuro Matsunaga¹, Masanobu Morita¹, Yukihiro Tsuchiya², Yasuo Watanabe², Hideki Sumimoto³, Hozumi Motohashi⁴, Takaaki Akaike¹ (¹Dept. Environ. Med. Mol. Toxicol., Tohoku Univ., Grad. Sch. Med., ²Dept. Pharm., Showa Pharm. Univ., ³Dept. Biochem., Kyushu Univ., Grad. Sch. Med. Sci., ⁴Dept. Gene Exp. Reg., IDAC, Tohoku Univ.)

Reactive oxygen species (ROS) and nitric oxide (NO) generated by NADPH oxidase (NOX) and NO synthase (NOS) have important role in the host defense for various pathogens. Our previous report showed a potent anti-bacterial effect of ROS and NO that was identified clearly during Salmonella infection. It is now unexpectedly found that NOS and NOX can transfer the electrons to sulfur rather than oxygen, and super sulfide species like reactive persulfides generated thereby appears to be involved in NOS- and NOX-dependent anti-Salmonella activity. We thus aimed further to elucidate the mechanisms of supersulfide production by NOS and NOX and its anti-bacterial consequences. HEK293T cells overexpressing either three NOS isoforms (nNOS, eNOS, iNOS) or two NOX isoforms (NOX2, NOX4) were treated with oxidized glutathione trisulfide (GS-S-SG), which resulted in a markedly increased reactive persulfides in a manner depending on each enzyme expression. Recombinant nNOS and eNOS in the presence of NADPH reduce GS-S-SG and oxidatively activate (or reactivate) the super sulfide to form persulfides with elongated polysulfide chains (e.g., GS-SH and GS-S-SH) having higher redox activity in vitro. We herein propose a novel function of NOS and NOX as an NADPH-dependent sulfur oxidoreductase (NSOR) to potentiate the host defense functions possibly through activation of various super sulfur species.