title: Endogenous nitrated nucleotide is a key mediator of autophagy and innate defense against bacteria.
abstract: Autophagy is a cellular self-catabolic process wherein organelles, macromolecules, and invading microbes are sequestered in autophagosomes that fuse with lysosomes. In this study, we uncover the role of nitric oxide (NO) as a signaling molecule for autophagy induction via its downstream mediator, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP). We found that 8-nitro-cGMP-induced autophagy is mediated by Lys63-linked polyubiquitination and that endogenous 8-nitro-cGMP promotes autophagic exclusion of invading group A Streptococcus (GAS) from cells. 8-nitro-cGMP can modify Cys residues by S-guanylation of proteins. We showed that intracellular GAS is modified with S-guanylation extensively in autophagosomes-like vacuoles, suggesting the role of S-guanylation as a marker for selective autophagic degradation. This finding is supported by the fact that S-guanylated bacteria were selectively marked with polyubiquitin, a known molecular tag for selective transport to autophagosomes. These results collectively indicate that 8-nitro-cGMP plays a crucial role in cytoprotection during bacterial infections or inflammations via autophagy upregulation.
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Ito
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Section of Bacterial Pathogenesis, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nozawa
authors.affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Shigemoto
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sawa
authors.affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Shahzada
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Akashi
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Section of Bacterial Pathogenesis, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Aikawa
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sagara
authors.affiliation: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Akaike
authors.affiliation: Section of Bacterial Pathogenesis, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakagawa
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan. Electronic address: arimoto@biochem.tohoku.ac.jp.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Arimoto
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D001426:Bacterial Proteins / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D013297:Streptococcus pyogenes / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination
chemical_list: C525106:8-nitroguanosine 3',5'-cyclic monophosphate; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D001426:Bacterial Proteins; D008070:Lipopolysaccharides; D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; D025821:Polyubiquitin; D009569:Nitric Oxide; D007371:Interferon-gamma; D006152:Cyclic GMP