Myxococcus CsgA, Drosophila Sniffer, and human HSD10 are cardiolipin phospholipases

Genes Dev. 2015 Sep 15;29(18):1903-14. doi: 10.1101/gad.268482.115. Epub 2015 Sep 3.

Abstract

Myxococcus xanthus development requires CsgA, a member of the short-chain alcohol dehydrogenase (SCAD) family of proteins. We show that CsgA and SocA, a protein that can replace CsgA function in vivo, oxidize the 2'-OH glycerol moiety on cardiolipin and phosphatidylglycerol to produce diacylglycerol (DAG), dihydroxyacetone, and orthophosphate. A lipid extract enriched in DAGs from wild-type cells initiates development and lipid body production in a csgA mutant to bypass the mutational block. This novel phospholipase C-like reaction is widespread. SCADs that prevent neurodegenerative disorders, such as Drosophila Sniffer and human HSD10, oxidize cardiolipin with similar kinetic parameters. HSD10 exhibits a strong preference for cardiolipin with oxidized fatty acids. This activity is inhibited in the presence of the amyloid β peptide. Three HSD10 variants associated with neurodegenerative disorders are inactive with cardiolipin. We suggest that HSD10 protects humans from reactive oxygen species by removing damaged cardiolipin before it induces apoptosis.

Keywords: CsgA; Drosophila Sniffer; HSD10; Myxococcus xanthus; cardiolipin; phospholipase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3-Hydroxyacyl CoA Dehydrogenases / genetics
  • 3-Hydroxyacyl CoA Dehydrogenases / metabolism*
  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / metabolism*
  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cardiolipins / metabolism
  • Diglycerides / metabolism
  • Dihydroxyacetone / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / enzymology
  • Escherichia coli / genetics
  • Humans
  • Lipid Droplets / metabolism
  • Membrane Proteins / metabolism
  • Mutation
  • Myxococcus / enzymology
  • Oxidation-Reduction
  • Phosphates / metabolism
  • Phosphatidylglycerols / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Substrate Specificity
  • Transferases (Other Substituted Phosphate Groups) / metabolism

Substances

  • Bacterial Proteins
  • Cardiolipins
  • CsgA protein, Myxococcus xanthus
  • Diglycerides
  • Drosophila Proteins
  • Membrane Proteins
  • Phosphates
  • Phosphatidylglycerols
  • Recombinant Proteins
  • sni protein, Drosophila
  • Alcohol Oxidoreductases
  • 3-Hydroxyacyl CoA Dehydrogenases
  • HSD17B10 protein, human
  • Transferases (Other Substituted Phosphate Groups)
  • cardiolipin synthetase
  • Dihydroxyacetone