Starvation Sensing by Mycobacterial RelA/SpoT Homologue Through Constitutive Surveillance of Translation

Authors

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

Document Type

Article

Publication Date

5-22-2023

Comments

This article is the author's final published version in Proceedings of the National Academy of Sciences, Volume 120, Issue 22, Article number e2302006120.

The published version is available at https://doi.org/10.1073/pnas.2302006120. Copyright © 2023 the Author(s). Published by PNAS

Abstract

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.

Recommended Citation

Li, Yunlong; Majumdar, Soneya; Treen, Ryan; Sharma, Manjuli R.; Corro, Jamie; Gamper, Howard B.; Manjari, Swati R.; Prusa, Jerome; Banavali, Nilesh K.; Stallings, Christina L.; Hou, Ya-Ming; Agrawal, Rajendra K.; and Ojha, Anil K., "Starvation Sensing by Mycobacterial RelA/SpoT Homologue Through Constitutive Surveillance of Translation" (2023). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 239.
https://jdc.jefferson.edu/bmpfp/239

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

37216503

Language

English