LplA1-dependent utilization of host lipoyl peptides enables Listeria cytosolic growth and virulence.
The bacterial pathogen Listeria monocytogenes replicates within the cytosol of mammalian cells. Mechanisms by which the bacterium exploits the host cytosolic environment for essential nutrients are poorly defined. L. monocytogenes is a lipoate auxotroph and must scavenge this critical cofactor, using lipoate ligases to facilitate attachment of the lipoyl moiety to metabolic enzyme complexes. Although the L. monocytogenes genome encodes two putative lipoate ligases, LplA1 and LplA2, intracellular replication and virulence require only LplA1. Here we show that LplA1 enables utilization of host-derived lipoyl peptides by L. monocytogenes. LplA1 is dispensable for growth in the presence of free lipoate, but necessary for growth on low concentrations of mammalian lipoyl peptides. Furthermore, we demonstrate that the intracellular growth defect of the DeltalplA1 mutant is rescued by addition of exogenous lipoic acid to host cells, suggesting that L. monocytogenes dependence on LplA1 is dictated by limiting concentrations of available host lipoyl substrates. Thus, the ability of L. monocytogenes and other intracellular pathogens to efficiently use host lipoyl peptides as a source of lipoate may be a requisite adaptation for life within the mammalian cell.
Keeney
Kristie M
KM
Department of Microbiology and Immunology, University of Michigan Medical School, 1150 W. Medical Center Drive, 5641 Medical Sciences II, Ann Arbor, MI 48109-0620, USA.
Stuckey
Jeanne A
JA
O'Riordan
Mary X D
MX
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism / Q000382:microbiology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D005816:Genetic Complementation Test; D007658:Ketone Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008087:Listeria / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D014774:Virulence / Q000235:genetics
D001426:Bacterial Proteins; D008074:Lipoproteins; D008565:Membrane Proteins; D010455:Peptides; C089935:lplA protein, bacteria; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+)