Listeria monocytogenes multidrug resistance transporters and cyclic di-AMP, which contribute to type I interferon induction, play a role in cell wall stress.
The intracellular bacterial pathogen Listeria monocytogenes activates a robust type I interferon response upon infection. This response is partially dependent on the multidrug resistance (MDR) transporter MdrM and relies on cyclic-di-AMP (c-di-AMP) secretion, yet the functions of MdrM and cyclic-di-AMP that lead to this response are unknown. Here we report that it is not MdrM alone but a cohort of MDR transporters that together contribute to type I interferon induction during infection. In a search for a physiological function of these transporters, we revealed that they play a role in cell wall stress responses. A mutant with deletion of four transporter genes (ΔmdrMTAC) was found to be sensitive to sublethal concentrations of vancomycin due to an inability to produce and shed peptidoglycan under this stress. Remarkably, c-di-AMP is involved in this phenotype, as overexpression of the c-di-AMP phosphodiesterase (PdeA) resulted in increased susceptibility of the ΔmdrMTAC mutant to vancomycin, whereas overexpression of the c-di-AMP diadenylate cyclase (DacA) reduced susceptibility to this drug. These observations suggest a physiological association between c-di-AMP and the MDR transporters and support the model that MDR transporters mediate c-di-AMP secretion to regulate peptidoglycan synthesis in response to cell wall stress.
Department of Molecular Microbiology and Biotechnology, The George S. Wise Life Sciences Faculty, Tel Aviv University, Tel Aviv, Israel.
Millie
M
Kaplan Zeevi
Nirit S
NS
Shafir
Shira
S
Shaham
Sivan
S
Friedman
Nadejda
N
Sigal
Ran
R
Nir Paz
Ivo G
IG
Boneca
Anat A
AA
Herskovits
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002473:Cell Wall / Q000502:physiology*; D015226:Dinucleoside Phosphates / Q000235:genetics / Q000378:metabolism*; D024901:Drug Resistance, Multiple, Bacterial; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008089:Listeria monocytogenes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological
D018435:ATP Binding Cassette Transporter, Subfamily B; D000900:Anti-Bacterial Agents; D015226:Dinucleoside Phosphates; D007370:Interferon Type I; C528998:cyclic diadenosine phosphate; D016899:Interferon-beta