title: (p)ppGpp, a Small Nucleotide Regulator, Directs the Metabolic Fate of Glucose in Vibrio cholerae.
abstract: When V. cholerae encounters nutritional stress, it activates (p)ppGpp-mediated stringent response. The genes relA and relV are involved in the production of (p)ppGpp, whereas the spoT gene encodes an enzyme that hydrolyzes it. Herein, we show that the bacterial capability to produce (p)ppGpp plays an essential role in glucose metabolism. The V. cholerae mutants defective in (p)ppGpp production (i.e. ΔrelAΔrelV and ΔrelAΔrelVΔspoT mutants) lost their viability because of uncontrolled production of organic acids, when grown with extra glucose. In contrast, the ΔrelAΔspoT mutant, a (p)ppGpp overproducer strain, exhibited better growth in the presence of the same glucose concentration. An RNA sequencing analysis demonstrated that transcriptions of genes consisting of an operon for acetoin biosynthesis were markedly elevated in N16961, a seventh pandemic O1 strain, but not in its (p)ppGpp(0) mutant during glucose-stimulated growth. Transposon insertion in acetoin biosynthesis gene cluster resulted in glucose-induced loss of viability of the ΔrelAΔspoT mutant, further suggesting the crucial role of acetoin production in balanced growth under glucose-rich environments. Additional deletion of the aphA gene, encoding a negative regulator for acetoin production, failed to rescue the (p)ppGpp(0) mutant from the defective glucose-mediated growth, suggesting that (p)ppGpp-mediated acetoin production occurs independent of the presence of AphA. Overall, our results reveal that (p)ppGpp, in addition to its well known role as a stringent response mediator, positively regulates acetoin production that contributes to the successful glucose metabolism and consequently the proliferation of V. cholerae cells under a glucose-rich environment, a condition that may mimic the human intestine.
authors.affiliation: From the Department of Microbiology and Immunology, Brain Korea 21 PLUS Project for Medical Science and.
authors.forename: Young Taek
authors.initials: YT
authors.lastname: Oh
authors.affiliation: From the Department of Microbiology and Immunology, Brain Korea 21 PLUS Project for Medical Science and.
authors.forename: Kang-Mu
authors.initials: KM
authors.lastname: Lee
authors.affiliation: From the Department of Microbiology and Immunology, Brain Korea 21 PLUS Project for Medical Science and.
authors.forename: Wasimul
authors.initials: W
authors.lastname: Bari
authors.affiliation: the Marian University College of Osteopathic Medicine, Indianapolis, Indiana 46222.
authors.forename: David M
authors.initials: DM
authors.lastname: Raskin
authors.affiliation: From the Department of Microbiology and Immunology, Brain Korea 21 PLUS Project for Medical Science and the Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 120-752, Korea and sangsun_yoon@yuhs.ac.
authors.forename: Sang Sun
authors.initials: SS
authors.lastname: Yoon
mesh_terms: D000093:Acetoin / Q000378:metabolism*; D000143:Acids / Q000378:metabolism; D002470:Cell Survival; D005285:Fermentation; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D006158:Guanosine Pentaphosphate / Q000494:pharmacology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D012329:RNA, Bacterial / Q000235:genetics; D014734:Vibrio cholerae / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*
chemical_list: D000143:Acids; D012329:RNA, Bacterial; D006158:Guanosine Pentaphosphate; D000093:Acetoin; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases; D005947:Glucose
keywords: (p)ppGpp; Vibrio cholerae; acetoin fermentation; bacterial metabolism; bacterial pathogenesis; carbohydrate metabolism; stress response; stringent response