Proteasomal control of cytokinin synthesis protects Mycobacterium tuberculosis against nitric oxide

Mol Cell. 2015 Mar 19;57(6):984-994. doi: 10.1016/j.molcel.2015.01.024. Epub 2015 Feb 26.


One of several roles of the Mycobacterium tuberculosis proteasome is to defend against host-produced nitric oxide (NO), a free radical that can damage numerous biological macromolecules. Mutations that inactivate proteasomal degradation in Mycobacterium tuberculosis result in bacteria that are hypersensitive to NO and attenuated for growth in vivo, but it was not known why. To elucidate the link between proteasome function, NO resistance, and pathogenesis, we screened for suppressors of NO hypersensitivity in a mycobacterial proteasome ATPase mutant and identified mutations in Rv1205. We determined that Rv1205 encodes a pupylated proteasome substrate. Rv1205 is a homolog of the plant enzyme LONELY GUY, which catalyzes the production of hormones called cytokinins. Remarkably, we report that an obligate human pathogen secretes several cytokinins. Finally, we determined that the Rv1205-dependent accumulation of cytokinin breakdown products is likely responsible for the sensitization of Mycobacterium tuberculosis proteasome-associated mutants to NO.

Publication types

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

MeSH terms

  • Aldehydes / metabolism
  • Aminohydrolases / genetics
  • Aminohydrolases / metabolism*
  • Animals
  • Arabidopsis Proteins / metabolism
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Cytokinins / biosynthesis*
  • Cytokinins / metabolism
  • Host-Pathogen Interactions
  • Mice, Inbred C57BL
  • Mutation
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / metabolism*
  • Mycobacterium tuberculosis / pathogenicity
  • Nitric Oxide / metabolism*
  • Nitric Oxide / pharmacology
  • Proteasome Endopeptidase Complex / metabolism*
  • Suppression, Genetic


  • Aldehydes
  • Arabidopsis Proteins
  • Bacterial Proteins
  • Cytokinins
  • Nitric Oxide
  • Proteasome Endopeptidase Complex
  • Aminohydrolases
  • cytokinin riboside 5'-monophosphate phosphoribohydrolase, Arabidopsis