Persulfide synthases that are functionally coupled with translation mediate sulfur respiration in mammalian cells

We have studied the signalling mechanisms and physiological roles of 8-nitro-cGMP and found that the signalling by this compound is regulated by cysteine persulfide in cells

Shigemoto Fujii; Tomohiro Sawa; Hozumi Motohashi; Takaaki Akaike


Scholarcy highlights

  • Reactive persulfide species including cysteine persulfide are found in abundant quantities in both prokaryotic and eukaryotic cells
  • We identified two transsulfuration enzymes, cystathionine β-synthase and cystathionine γ-lyase, that participate in endogenous CysSSH formation
  • To understand how protein polysulfidation occurs in cells, we studied whether cysteinyl-tRNA synthetase can catalyse direct incorporation of CysSSH/Cys-(S)n-H into tRNA
  • We found greatly reduced CysSSH and CysSSSH synthesis in various lysine-toalanine mutants, compared with the wild type, at K73A, K76A, K266A, K269A, and double mutants K73/76A and K266/269A, of Escherichia coli CARS
  • Activity of one of the clones, with a 30 bp deletion and a 8 bp insertion downstream of the translation-initiating codon in the CARS2 first exon, was analysed by using LC-MS-MS methods and the results showed that CysS-(S)n-H and glutathione persulfide levels were significantly decreased in CARS2 KO cells, implying that CARS2 was a major producer of persulfide/ polysulfide species
  • In CARS2 KO cells, CSE and cystathionine βsynthase knockdown led to lower cysteine levels but not to lower persulfide production. These findings show that the metabolic pathways mediated by CSE/CBS in each cell line provide cysteine, regardless of CARS2 expression
  • We have detailed the novel role of cysteine persulfide produced by CARS2 in the regulation of mitochondrial functions, including sulfur respiration

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