The perilipin-like PPE15 protein in Mycobacterium tuberculosis is required for triacylglycerol accumulation under dormancy-inducing conditions.
Mycobacterium tuberculosis (Mtb) causes latent tuberculosis infection in one-third of the world population and remains quiescent in the human body for decades. The dormant pathogen accumulates lipid droplets containing triacylglycerol (TAG). In mammals, perilipin regulates lipid droplet homeostasis but no such protein has been identified in Mtb. We identified an Mtb protein (PPE15) that showed weak amino acid sequence identities with mammalian perilipin-1 and was upregulated in Mtb dormancy. We generated a ppe15 gene-disrupted mutant of Mtb and examined its ability to metabolically incorporate radiolabeled oleic acid into TAG, accumulate lipid droplets containing TAG and develop phenotypic tolerance to rifampicin in two in vitro models of dormancy including a three-dimensional human granuloma model. The mutant showed a significant decrease in the biosynthesis and accumulation of lipid droplets containing TAG and in its tolerance of rifampicin. Complementation of the mutant with a wild-type copy of the ppe15 gene restored the lost phenotypes. We designate PPE15 as mycobacterial perilipin-1 (MPER1). Our findings suggest that the MPER1 protein plays a critical role in the homeostasis of TAG -containing lipid droplets in Mtb and influences the entry of the pathogen into a dormant state.
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA.|Department of Biology, Indiana University-Purdue University Fort Wayne, Fort Wayne, IN 46805, USA.
Jaiyanth
0000-0002-3605-687X
J
Daniel
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA.
Nidhi
N
Kapoor
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA.
Tatiana
T
Sirakova
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA.
Rajesh
R
Sinha
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA.
Pappachan
P
Kolattukudy
D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D054884:Host-Pathogen Interactions; D006801:Humans; D055985:Latent Tuberculosis / Q000382:microbiology; D050356:Lipid Metabolism; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism*; D000070778:Perilipin-1 / Q000235:genetics / Q000378:metabolism*; D020539:Sequence Analysis, Protein / Q000379:methods; D014280:Triglycerides / Q000378:metabolism*
D000942:Antigens, Bacterial; D000070778:Perilipin-1; D014280:Triglycerides