Starvation sensing by mycobacterial RelA/SpoT homologue through constitutive surveillance of translation

Yunlong Li, Soneya Majumdar, Ryan Treen, Manjuli R. Sharma, Jamie Corro, Howard B. Gamper, Swati R. Manjari, Jerome Prusa, Nilesh K. Banavali, Christina L. Stallings, Ya Ming Hou, Rajendra K. Agrawal, Anil K. Ojha

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


The stringent response, which leads to persistence of nutrient-starved mycobacteria, is induced by activation of the RelA/SpoT homolog (Rsh) upon entry of a deacylated-tRNA in a translating ribosome. However, the mechanism by which Rsh identifies such ribosomes in vivo remains unclear. Here, we show that conditions inducing ribosome hibernation result in loss of intracellular Rsh in a Clp protease–dependent manner. This loss is also observed in nonstarved cells using mutations in Rsh that block its interaction with the ribosome, indicating that Rsh association with the ribosome is important for Rsh stability. The cryo-EM structure of the Rsh-bound 70S ribosome in a translation initiation complex reveals unknown interactions between the ACT domain of Rsh and components of the ribosomal L7/L12 stalk base, suggesting that the aminoacylation status of A-site tRNA is surveilled during the first cycle of elongation. Altogether, we propose a surveillance model of Rsh activation that originates from its constitutive interaction with the ribosomes entering the translation cycle.

Original languageEnglish
Article numbere2302006120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number22
StatePublished - May 30 2023


  • Mpy
  • Mycobacterium
  • RelA/SpoT
  • ribosome hibernation
  • zinc


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