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Cyclic di-GMP signaling and the Type IV macromolecule secretion system in Xanthomonas citri

Abstract

In this Project we propose to develop two lines of research into the biology of the phytopathogen Xanthomonas citri (Xac), the causative agent of citrus canker. i) Metabolism of the second messenger c-di-GMP: synthesis, degradation and receptors. Bacteria can adopt multiple lifestyles. At one extreme, individual cells can undergo planktonic growth in liquid medium in which they use flagella to swim in the direction of chemo-attractants or away from chemo-repellents. At the other extreme, another lifestyle involves growth on a surface as part of a static community, often called a biofilm. The ability to switch between these and intermediate lifestyles requires the coordination of a series of developmental events and complex physiological behaviors such as quorum sensing, several types of motility, adhesion to surfaces, secretion of exopolysaccharides, surfactants and extracellular enzymes and the production of virulence factors. There is a wealth of evidence that the dinucleotide bis(3´à5´) cyclic di-GMP (c-di-GMP) plays a central role in these processes in bacteria. C-di-GMP is synthesized by diguanylate cyclases (GGDEF domains), degraded by two classes of phosphodiesterases (EAL and HD-GYP domains), and many different c-di-GMP receptor families have been characterized (PilZ, FleQ, CLP, non-catalystic GGDEF and EAL domains as well as riboswitches). The phytopathogen Xanthomonas citri (Xac), that causes citrus canker, will be used as a model to study the complexity of c-di-GMP mediated bacterial signaling networks. The Xac genome codes for several dozen potential cyclases, phosphodiesterases and c-di-GMP receptors, the majority of which are covalently or non-covalently associated with other protein domains involved in a large variety of molecular signaling activities. Our long-term challenge is to understand the structure-function relationships that control cyclase and phosphodiesterase enzymatic activity as well as the principles that regulate receptor affinity for this second messenger. We are also interested in understanding the variety of interactions that these domains undergo with other domain families and how these interactions modulate cyclase and phosphodiesterase activities and receptor affinities. ii) Type IV secretion systems. Many pathogenic bacteria use macromolecular secretion systems to transfer virulence factors into host cells. In this project we plan to continue our studies into the structure and function of the Xac Type IV secretion system (T4SS). Its large size (multiple copies of at least a dozen different subunits and a molecular mass of > 1 megaDalton) creates significant challenges for structural studies. Another major challenge is to identify and characterize specific substrates secreted by this system. In our studies, we propose to employ a variety of experimental methods including X-ray crystallography, nuclear magnetic resonance (NMR), SAXS, molecular dynamics simulations, statistical coupling analysis (SCA), the production and characterization of gene knock-outs, enzymology and gene expression studies (AU)

Articles published in Pesquisa FAPESP Magazine about the research grant:
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Articles published in other media outlets (20 total):
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Portal Exame: Pesquisadores desvendam como bactéria oportunista derrota competidoras (11/Dec/2019)
Programa InfoSalud (Argentina): Científicos develan cómo una bacteria oportunista derrota a sus competidoras (30/Jan/2020)
Revista Ecológico online: Pesquisadores desvendam como bactéria oportunista derrota competidoras (17/Dec/2019)
Sou Ecológico: Pesquisadores desvendam como bactéria oportunista derrota competidoras (17/Dec/2019)
LabNetwork: Pesquisadores desvendam como bactéria oportunista derrota competidoras (12/Dec/2019)
Algomais online: Pesquisadores desvendam como bactéria oportunista derrota competidoras (12/Dec/2019)
Brasil CT&I: Pesquisadores desvendam como bactéria oportunista derrota competidoras (12/Dec/2019)
MSN: Pesquisadores desvendam como bactéria oportunista derrota competidoras (11/Dec/2019)
Diário da Saúde: Bactéria contra bactéria pode render novos antibióticos (11/Dec/2019)
Confap - Conselho Nacional das Fundações Estaduais de Amparo à Pesquisa: Pesquisadores desvendam como bactéria oportunista derrota competidores (11/Dec/2019)
Esteta : Pesquisadores desvendam como bactéria oportunista derrota competidoras (11/Dec/2019)
Planeta online: Descoberto como bactéria oportunista de hospitais elimina oponentes (11/Dec/2019)
Jornal da Ciência online: Pesquisadores desvendam como bactéria oportunista derrota competidoras (11/Dec/2019)
Portal da Enfermagem: Pesquisadores desvendam como bactéria oportunista derrota competidoras (11/Dec/2019)
Programa InfoSalud (Argentina): Investigadores revelan como bacterias oportunistas derrotan a competidoras (11/Dec/2019)
Phys.Org (Reino Unido): Researchers show how opportunistic bacterium defeats competitors (10/Dec/2019)
Science Codex: Researchers show how opportunistic bacterium defeats competitors (10/Dec/2019)
Brightsurf: Researchers show how opportunistic bacterium defeats competitors (10/Dec/2019)
7thSpace: Researchers show how opportunistic bacterium defeats competitors (10/Dec/2019)
Long Room (EUA): Researchers show how opportunistic bacterium defeats competitors (12/Oct/2019)

Scientific publications (13)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CENENS, WILLIAM; ANDRADE, MAXUEL O.; LLONTOP, EDGAR; ALVAREZ-MARTINEZ, CRISTINA E.; SGRO, GERMAN G.; FARAH, CHUCK S. Bactericidal type IV secretion system homeostasis in Xanthomonas citri. PLOS PATHOGENS, v. 16, n. 5 MAY 2020. Web of Science Citations: 0.
CESETI, LUCAS M.; DE SANTANA, ELIANE S.; RATAGAMI, CAMILA Y.; BARREIROS, YASMIN; LIMA, LIDIA DOS PASSOS; DUNGER, GERMAN; FARAH, CHUCK S.; ALVAREZ-MARTINEZ, CRISTINA E. The Xanthomonas citri pv. citri Type VI Secretion System is Induced During Epiphytic Colonization of Citrus. Current Microbiology, v. 76, n. 10, p. 1105-1111, OCT 2019. Web of Science Citations: 0.
BAYER-SANTOS, ETHEL; CENENS, WILLIAM; MATSUYAMA, BRUNO YASUI; OKA, GABRIEL UMAJI; DI SESSA, GIANCARLO; MININEL, IZABEL DEL VALLE; ALVES, TIAGO LUBIANA; FARAH, CHUCK SHAKER. The opportunistic pathogen Stenotrophomonas maltophilia utilizes a type IV secretion system for interbacterial killing. PLOS PATHOGENS, v. 15, n. 9 SEP 2019. Web of Science Citations: 1.
SGRO, GERMAN G.; COSTA, TIAGO R. D.; CENENS, WILLIAM; SOUZA, DIORGE P.; CASSAGO, ALEXANDRE; DE OLIVEIRA, LUCIANA COUTINHO; SALINAS, ROBERTO K.; PORTUGAL, V, RODRIGO; FARAH, CHUCK S.; WAKSMAN, GABRIEL. Cryo-EM structure of the bacteria-killing type IV secretion system core complex from Xanthomonas citri. NATURE MICROBIOLOGY, v. 3, n. 12, p. 1429-1440, DEC 2018. Web of Science Citations: 11.
TEIXEIRA, RAPHAEL D.; GUZZO, CRISTIANE R.; AREVALO, SANTIAGO JUSTO; ANDRADE, MAXUEL O.; ABRAHAO, JOSIELLE; DE SOUZA, ROBSON F.; FARAH, CHUCK S. A bipartite periplasmic receptor-diguanylate cyclase pair (XAC2383-XAC2382) in the bacterium Xanthomonas citri. Journal of Biological Chemistry, v. 293, n. 27, p. 10767-10781, JUL 6 2018. Web of Science Citations: 0.
BAYER-SANTOS, ETHEL; LIMA, LIDIA DOS PASSOS; CESETI, LUCAS DE MORAES; RATAGAMI, CAMILA YURI; DE SANTANA, ELIANE SILVA; DA SILVA, ALINE MARIA; FARAH, CHUCK SHAKER; ALVAREZ-MARTINEZ, CRISTINA ELISA. Xanthomonas citri T6SS mediates resistance to Dictyostelium predation and is regulated by an ECF sigma factor and cognate Ser/Thr kinase. ENVIRONMENTAL MICROBIOLOGY, v. 20, n. 4, SI, p. 1562-1575, APR 2018. Web of Science Citations: 6.
OLIVEIRA, LUCIANA COUTINHO; SOUZA, DIORGE PAULO; OKA, GABRIEL UMAJI; LIMA, FILIPE DA SILVA; OLIVEIRA, RONALDO JUNIO; FAVARO, DENIZE CRISTINA; WIENK, HANS; BOELENS, ROLF; FARAH, CHUCK SHAKER; SALINAS, ROBERTO KOPKE. VirB7 and VirB9 Interactions Are Required for the Assembly and Antibacterial Activity of a Type IV Secretion System. Structure, v. 24, n. 10, p. 1707-1718, OCT 4 2016. Web of Science Citations: 3.
ABIKO, LAYARA AKEMI; VITALE, PHELIPE M.; FAVARO, DENIZE C.; HAUK, PRICILA; LI, DA-WEI; YUAN, JIAQI; BRUSCHWEILER-LI, LEI; SALINAS, ROBERTO K.; BRUSCHWEILER, RAFAEL. Model for the allosteric regulation of the Na+/Ca2+ exchanger NCX. PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, v. 84, n. 5, p. 580-590, MAY 2016. Web of Science Citations: 3.
DUNGER, GERMAN; LLONTOP, EDGAR; GUZZO, CRISTIANE R.; FARAH, CHUCK S. The Xanthomonas type IV pilus. Current Opinion in Microbiology, v. 30, p. 88-97, APR 2016. Web of Science Citations: 10.
SOUZA, DIORGE P.; OKA, GABRIEL U.; ALVAREZ-MARTINEZ, CRISTINA E.; BISSON-FILHO, ALEXANDRE W.; DUNGER, GERMAN; HOBEIKA, LISE; CAVALCANTE, NAYARA S.; ALEGRIA, MARCOS C.; BARBOSA, LEANDRO R. S.; SALINAS, ROBERTO K.; GUZZO, CRISTIANE R.; FARAH, CHUCK S. Bacterial killing via a type IV secretion system. NATURE COMMUNICATIONS, v. 6, MAR 2015. Web of Science Citations: 40.
OLIVEIRA, MAYCON C.; TEIXEIRA, RAPHAEL D.; ANDRADE, MAXUEL O.; PINHEIRO, GLAUCIA M. S.; RAMOS, CARLOS H. I.; FARAH, CHUCK S. Cooperative Substrate Binding by a Diguanylate Cyclase. Journal of Molecular Biology, v. 427, n. 2, p. 415-432, JAN 30 2015. Web of Science Citations: 10.
DUNGER, GERMAN; GUZZO, CRISTIANE R.; ANDRADE, MAXUEL O.; JONES, JEFFREY B.; FARAH, CHUCK S. Xanthomonas citri subsp citri Type IV Pilus Is Required for Twitching Motility, Biofilm Development, and Adherence. MOLECULAR PLANT-MICROBE INTERACTIONS, v. 27, n. 10, p. 1132-1147, OCT 2014. Web of Science Citations: 22.
GUZZO, CRISTIANE R.; DUNGER, GERMAN; SALINAS, ROBERTO KOPKE; FARAH, CHUCK S. Structure of the PilZ-FimX(EAL)-c-di-GMP Complex Responsible for the Regulation of Bacterial Type IV Pilus Biogenesis. Journal of Molecular Biology, v. 425, n. 12, p. 2174-2197, JUN 26 2013. Web of Science Citations: 24.

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