Abstract
Listeria monocytogenes (Lm) is a saprophyte and intracellular pathogen. Transition to the pathogenic state relies on sensing of host-derived metabolites, yet it remains unclear how these are recognized and how they mediate virulence gene regulation. We previously found that low availability of isoleucine signals Lm to activate the virulent state. This response is dependent on CodY, a global regulator and isoleucine sensor. Isoleucine-bound CodY represses metabolic pathways including branched-chain amino acids (BCAA) biosynthesis, however under BCAA depletion, as occurs during infection, BCAA biosynthesis is upregulated and isoleucine-unbound CodY activates virulence genes. While isoleucine was revealed as an important input signal, it was not identified how internal levels are controlled during infection. Here we show that Lm regulates BCAA biosynthesis via CodY and via a riboregulator located upstream to the BCAA biosynthesis genes, named Rli60. rli60 is transcribed when BCAA levels drop, forming a ribosome-mediated attenuator that cis-regulates the downstream genes according to BCAA supply. Notably, we found that Rli60 restricts BCAA production, essentially starving Lm, a mechanism that is directly linked to virulence, as it controls the internal isoleucine pool and thereby CodY activity. This controlled BCAA auxotrophy likely evolved to enable isoleucine to serve as a host signal and virulence effector.
| Original language | English |
|---|---|
| Article number | e1007283 |
| Journal | PLoS Genetics |
| Volume | 14 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2018 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2018 Brenner et al.
Funding
MB was supported by The Joan and Jaime Constantiner Institute for Molecular Genetics. LL was supported by the Tel-Aviv University “Argentina honors PhD program”, supported by the Friends of Tel-Aviv University in Argentina. This work was supported by the research grant (R01AI109048) from the US National Institute of Allergy and Infectious Diseases to AAH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Tina Henkin and Abraham L. Sonenshein for helpful discussions. We thank Adi Millman for helping with the prediction of the RNA structures and Jörg Vogel for sharing his 5'-RACE protocol. We also thank our lab members; Sivan Friedman, Anna Pasechnek, Lev Rabinovich and Oded Mizrachi for their help.
| Funders | Funder number |
|---|---|
| National Institute of Allergy and Infectious Diseases | R01AI109048 |
