Temporal and evolutionary dynamics of two-component signaling pathways

Salazar, Michael E.; Laub, Michael T.

doi:10.1016/j.mib.2014.12.003

Cited by 76 publications

(61 citation statements)

References 51 publications

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“…Two component systems typically consist of a bifunctional sensor kinase and a cognate response regulator (Salazar and Laub, 2015). The sensor kinase perceives an extracellular signal and activates its cognate response regulator through a two-step phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

The Conserved Actinobacterial Two-Component System MtrAB Coordinates Chloramphenicol Production with Sporulation in Streptomyces venezuelae NRRL B-65442

et al. 2017

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Streptomyces bacteria make numerous secondary metabolites, including half of all known antibiotics. Production of antibiotics is usually coordinated with the onset of sporulation but the cross regulation of these processes is not fully understood. This is important because most Streptomyces antibiotics are produced at low levels or not at all under laboratory conditions and this makes large scale production of these compounds very challenging. Here, we characterize the highly conserved actinobacterial two-component system MtrAB in the model organism Streptomyces venezuelae and provide evidence that it coordinates production of the antibiotic chloramphenicol with sporulation. MtrAB are known to coordinate DNA replication and cell division in Mycobacterium tuberculosis where TB-MtrA is essential for viability but MtrB is dispensable. We deleted mtrB in S. venezuelae and this resulted in a global shift in the metabolome, including constitutive, higher-level production of chloramphenicol. We found that chloramphenicol is detectable in the wild-type strain, but only at very low levels and only after it has sporulated. ChIP-seq showed that MtrA binds upstream of DNA replication and cell division genes and genes required for chloramphenicol production. dnaA, dnaN, oriC, and wblE (whiB1) are DNA binding targets for MtrA in both M. tuberculosis and S. venezuelae. Intriguingly, over-expression of TB-MtrA and gain of function TB- and Sv-MtrA proteins in S. venezuelae also switched on higher-level production of chloramphenicol. Given the conservation of MtrAB, these constructs might be useful tools for manipulating antibiotic production in other filamentous actinomycetes.

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Section: Introductionmentioning

confidence: 99%

The Conserved Actinobacterial Two-Component System MtrAB Coordinates Chloramphenicol Production with Sporulation in Streptomyces venezuelae NRRL B-65442

et al. 2017

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“…Many two-component signaling pathways also have feedback loops, both negative and positive. Active, phosphorylated response regulators will often promote the transcription of themselves and their cognate kinases, whereas some activate the expression of factors that downregulate pathway output (Shin et al, 2006;Miyashiro and Goulian, 2008;Lippa and Goulian, 2009;Ray and Igoshin, 2010;Gao and Stock, 2013b;Salazar and Laub, 2015). The cross-regulation of different two-component systems has also been observed in which a downstream target of one pathway modulates the phosphorylation state or activity of another pathway (Eguchi et al, 2007;Eguchi et al, 2012;Chen and Groisman, 2013).…”

Section: Introductionmentioning

confidence: 99%

The small membrane protein MgrB regulates PhoQ bifunctionality to control PhoP target gene expression dynamics

Salazar

Podgornaia

Laub

2016

Molecular Microbiology

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In Escherichia coli and other γ-proteobacteria, the PhoQ-PhoP two-component signaling system responds to low extracellular Mg and cationic antimicrobial peptides. On transition to inducing conditions, the expression of PhoP-dependent genes increases rapidly, but then decays to a new, intermediate steady-state level, a phenomenon often referred to as partial adaptation. The molecular basis for this partial adaptation has been unclear. Here, using time-lapse fluorescence microscopy to examine PhoP-dependent gene expression in individual E. coli cells we show that partial adaptation arises through a negative feedback loop involving the small protein MgrB. When E. coli cells are shifted to low Mg , PhoQ engages in multiple rounds of autophosphorylation and phosphotransfer to PhoP, which, in turn, drives the expression of mgrB. MgrB then feeds back to inhibit the kinase activity of PhoQ. PhoQ is bifunctional such that, when not active as a kinase, it can stimulate the dephosphorylation of PhoP. Thus, MgrB drives the inactivation of PhoP and the observed adaptation in PhoP-dependent gene expression. Our results clarify the source of feedback inhibition in the E. coli PhoQ-PhoP system and reveal how exogenous factors, such as MgrB, can combine with a canonical two-component signaling pathway to produce complex temporal dynamics in target gene expression.

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“…The complexity of regulatory circuitry determines the performance characteristics of the network and allows multiple regulatory inputs. The presence of autoregulatory and feedforward loops influences the responsiveness, cell-to-cell variation and temporal dynamics of gene expression within a network (Alon, 2007; Salazar and Laub, 2015). …”

Section: Regulatory Network and Signal Integrationmentioning

confidence: 99%

Discrimination and Integration of Stress Signals by Pathogenic Bacteria

Fang

Frawley

Tapscott

et al. 2016

Cell Host & Microbe

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For pathogenic bacteria, the ability to sense and respond to environmental stresses encountered within the host is critically important, allowing them to adapt to changing conditions and express virulence genes appropriately. This review considers the diverse molecular mechanisms by which stress conditions are sensed by bacteria, how related signals are discriminated and how stress responses are integrated, highlighting recent studies in selected bacterial pathogens of clinical relevance.

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Temporal and evolutionary dynamics of two-component signaling pathways

Cited by 76 publications

References 51 publications

The Conserved Actinobacterial Two-Component System MtrAB Coordinates Chloramphenicol Production with Sporulation in Streptomyces venezuelae NRRL B-65442

The Conserved Actinobacterial Two-Component System MtrAB Coordinates Chloramphenicol Production with Sporulation in Streptomyces venezuelae NRRL B-65442

The small membrane protein MgrB regulates PhoQ bifunctionality to control PhoP target gene expression dynamics

Discrimination and Integration of Stress Signals by Pathogenic Bacteria

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