Reactive Persulfides from Salmonella Typhimurium Downregulate Autophagy-Mediated Innate Immunity in Macrophages by Inhibiting Electrophilic Signaling

Shahzada Khan, Shigemoto Fujii, Tetsuro Matsunaga, Akira Nishimura, Katsuhiko Ono, Tomoaki Ida, Khandaker Ahtesham Ahmed, Tatsuya Okamoto, Hiroyasu Tsutsuki, Tomohiro Sawa, Takaaki Akaike

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Reactive persulfides such as cysteine persulfide and glutathione persulfide are produced by bacteria including Salmonella during sulfur metabolism. The biological significance of bacterial reactive persulfides in host-pathogen interactions still warrants investigation. We found that reactive persulfides produced by Salmonella Typhimurium LT2 regulate macrophage autophagy via metabolizing 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP), an electrophilic product of reactive oxygen species and nitric oxide signaling. 8-Nitro-cGMP signaling was required for efficient autophagy-mediated clearance of Salmonella from infected macrophages. In the infected cells, 8-nitro-cGMP caused cGMP adduct formation (S-guanylation) of bacterial surface proteins, which triggered recruitment of autophagy-related proteins p62 and LC3-II to the intracellular bacteria. We also found that Salmonella-produced reactive persulfides downregulated this autophagy by decreasing cellular 8-nitro-cGMP content, thereby inhibiting electrophilic signaling. These data reveal a pathogenic role of bacteria-derived reactive persulfides via suppression of anti-bacterial autophagy. Khan et al. found that reactive persulfides produced by Salmonella inhibit autophagy-mediated bacterial clearance by regulating electrophilic signaling. These data reveal a pathogenic role of bacteria-derived reactive persulfides via suppression of anti-bacterial autophagy.

Original languageEnglish
Pages (from-to)1403-1413.e4
JournalCell chemical biology
Volume25
Issue number11
DOIs
Publication statusPublished - 2018 Nov 15

Keywords

  • 8-nitroguanosine 3′,5′-cyclic monophosphate
  • autophagy
  • electrophilic signaling
  • host-pathogen interaction
  • reactive persulfides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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