Tyrosine phosphorylation coupling of one-carbon metabolism and virulence in an endogenous pathogen
Abstract
Endogenous pathogens can constrain virulence to ensure survival in the host. Pathogenic state can be controlled by metabolic responses to the prevailing microenvironment; however, the coupling and effector mechanisms are not well understood. Flux through the one-carbon metabolism (OCM) pathway can modulate virulence of the oral pathobiont Porphyromonas gingivalis , and here we show that this is controlled by tyrosine phosphorylation-dependent differential partitioning of gingipain proteases. The OCM essential precursor pABA inhibits the low molecular weight tyrosine phosphatase Ltp1, and consequently relieves inhibition of its cognate kinase, Ptk1. We found that in the absence of pABA, reduced Ptk1 kinase activity blocks extracellular release of gingipains. Surface retention of gingipains confers resistance to neutrophil mobilization and killing, and virulence in animal models of disease is elevated. Reciprocally, Ptk1 and gingipains are required for maximal flux through OCM, and Ptk1 can phosphorylate the OCM pathway enzymes GlyA and GcvT. Further, ALP, an alkaline phosphatase involved in synthesis of DHPPP, which combines with pABA to make DHP, is phosphorylated and activated by Ptk1. We propose, therefore, that although the primary function of Ptk1 is to maintain OCM balance, it mechanistically couples metabolism with tunable pathogenic potential through directing the location of proteolytic virulence factors.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Kendall S. Stocke
Department of Oral Immunology and Infectious Diseases, University of Louisville
Satya D. Pandey
Department of Oral Immunology and Infectious Diseases, University of Louisville
Shunying Jin
Department of Oral Immunology and Infectious Diseases, University of Louisville
John D. Perpich
Department of Oral Immunology and Infectious Diseases, University of Louisville
Lan Yakoumatos
Department of Oral Immunology and Infectious Diseases, University of Louisville
Hirotaka Kosaki
Department of Oral Immunology and Infectious Diseases, University of Louisville
Daniel W. Wilkey
Division of Nephrology and Hypertension, Department of Medicine, University of Louisville
Zackary R. Fitzsimonds
Department of Oral Immunology and Infectious Diseases, University of Louisville
Aruna Vashishta
Department of Oral Immunology and Infectious Diseases, University of Louisville
Ian Snider
Department of Oral Immunology and Infectious Diseases, University of Louisville
Mukesh K. Sriwastva
Department of Oral Immunology and Infectious Diseases, University of Louisville
Hong Li
Jiu-Zhen Jin
Department of Oral Immunology and Infectious Diseases, University of Louisville
Daniel P. Miller
Department of Oral Immunology and Infectious Diseases, University of Louisville
Michael L. Merchant
Division of Nephrology and Hypertension, Department of Medicine, University of Louisville
Juhi Bagaitkar
Center for Microbe and Immunity Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital
Silvia M. Uriarte
Department of Oral Immunology and Infectious Diseases, University of Louisville
Jan Potempa
Department of Oral Immunology and Infectious Diseases, University of Louisville
Richard J. Lamont
Department of Oral Immunology and Infectious Diseases, University of Louisville