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PASTA-kinase-mediated signaling drives accumulation of the peptidoglycan synthesis protein MurAA to promote cephalosporin resistance in Enterococcus faecalis. Mol Microbiol 2023 Dec;120(6):811-829

Date

09/09/2023

Pubmed ID

37688380

Pubmed Central ID

PMC10872757

DOI

10.1111/mmi.15150

Scopus ID

2-s2.0-85170564562 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

The bacterial PASTA kinase, IreK, is required for intrinsic cephalosporin resistance in the Gram-positive opportunistic pathogen, Enterococcus faecalis. IreK activity is enhanced in response to cell wall stress, such as cephalosporin exposure. The downstream consequences of IreK activation are not well understood in E. faecalis, but recent work in other low-GC Gram-positive bacteria demonstrated PASTA kinase-dependent regulation of MurAA, an enzyme that performs the first committed step in the peptidoglycan synthesis pathway. Here, we used genetic suppressor selections to identify MurAA as a downstream target of IreK signaling in E. faecalis. Using complementary genetic and biochemical approaches, we demonstrated that MurAA abundance is regulated by IreK signaling in response to physiologically relevant cell wall stress to modulate substrate flux through the peptidoglycan synthesis pathway. Specifically, the IreK substrate, IreB, promotes proteolysis of MurAA through a direct physical interaction in a manner responsive to phosphorylation by IreK. MurAB, a homolog of MurAA, also promotes MurAA proteolysis and interacts directly with IreB. Our results therefore establish a connection between the cell wall stress sensor IreK and one critical physiological output to modulate peptidoglycan synthesis and drive cephalosporin resistance.

Author List

Mascari CA, Little JL, Kristich CJ

Authors

Christopher J. Kristich PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Carly A. Mascari Postdoctoral Researcher in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Bacterial Proteins
Cell Wall
Cephalosporin Resistance
Enterococcus faecalis
Peptidoglycan
Phosphotransferases