Homocysteine Thiolactone from Translation Proofreading is an Endogenous Ligand for Cell-Cell Signaling by the Receptor SdiA

Authors

• Lorenzo Eugenio Leiva, Chapman University
• Roberto A. Zúñiga, Chapman University
• Gregory J. Phillips, University of Georgia
• Michael Ibba, Chapman UniversityFollow

Document Type

Article

Publication Date

7-16-2026

Abstract

Several widespread mechanisms enable cellular communication and coordinate the behavior of bacterial populations. The modules responsible for cellular communication are often found in matching pairs: an enzyme that synthesizes a signal molecule and a specific receptor that decodes it. A notable exception is Escherichia coli SdiA, a homolog of known N-acyl-homoserine lactone (AHL) receptors, for which no corresponding AHL synthase exists. SdiA is an orphan receptor that enables cross-talk by sensing AHLs from other bacterial species. In this work, we investigated whether homocysteine thiolactone (HTL), an AHL-like molecule arising from a proofreading reaction of methionyl tRNA synthetase (MetRS) to correct misactivation of homocysteine, participates in E. coli communication through SdiA. A comprehensive analysis of MetRS variants producing different levels of HTL revealed more extended lag periods at lower HTL levels, which were restored by HTL supplementation. SdiA mutants abolished the HTL-induced regulation of the transition from the lag to the exponential phase. Growth phenotypes were HTL specific and were not induced by supplementation of other non-endogenous AHLs previously characterized as SdiA ligands. The gene expression of gadY and rmf, regulated by SdiA, was modulated by HTL supplementation. Through differential scanning fluorimetry, we show the SdiA-HTL interaction in vitro. Together, our observations describe HTL as an SdiA ligand that modulates cell-cell communication in bacteria.

Comments

This article was originally published in mBio, volume 17, issue 8, in 2026. https://doi.org/10.1128/mbio.01407-26

Recommended Citation

Leiva LE, Zúñiga RA, Phillips GJ, Ibba M. 0. Homocysteine thiolactone from translation proofreading is an endogenous ligand for cell-cell signaling by the receptor SdiA. mBio 17:e01407-26. https://doi.org/10.1128/mbio.01407-26

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This work is licensed under a Creative Commons Attribution 4.0 License.