Mycobacterium tuberculosis RbpA protein is a new type of transcriptional activator that stabilizes the σ A -containing RNA polymerase holoenzyme

Hu, Yangbo; Morichaud, Zakia; Chen, Shiyun; Leonetti, Jean-Paul; Brodolin, Konstantin

doi:10.1093/nar/gks346

Cited by 64 publications

(135 citation statements)

References 51 publications

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“…We suggest that the N-terminal tail and/or RCD likely form additional interactions with RNAP. Interactions between RbpA and core RNAP have been proposed previously, and putative interactions have been mapped to two widely spaced regions of RNAP (18,27). However, our RbpA-SID/RPo structural model is completely incompatible with previous claims that RbpA interacts with RNAP either in the active-site channel near the Rif binding site (27,28) (Fig.…”

Section: Discussionmentioning

confidence: 49%

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Structural, functional, and genetic analyses of the actinobacterial transcription factor RbpA

Hubin

Tabib-Salazar

Humphrey

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Gene expression is highly regulated at the step of transcription initiation, and transcription activators play a critical role in this process. RbpA, an actinobacterial transcription activator that is essential in Mycobacterium tuberculosis (Mtb), binds selectively to group 1 and certain group 2 σ-factors. To delineate the molecular mechanism of RbpA, we show that the Mtb RbpA σ-interacting domain (SID) and basic linker are sufficient for transcription activation. We also present the crystal structure of the Mtb RbpA-SID in complex with domain 2 of the housekeeping σ-factor, σ A . The structure explains the basis of σ-selectivity by RbpA, showing that RbpA interacts with conserved regions of σ A as well as the nonconserved region (NCR), which is present only in housekeeping σ-factors. Thus, the structure is the first, to our knowledge, to show a protein interacting with the NCR of a σ-factor. We confirm the basis of selectivity and the observed interactions using mutagenesis and functional studies. In addition, the structure allows for a model of the RbpA-SID in the context of a transcription initiation complex. Unexpectedly, the structural modeling suggests that RbpA contacts the promoter DNA, and we present in vivo and in vitro studies supporting this finding. Our combined data lead to a better understanding of the mechanism of RbpA function as a transcription activator.RbpA | X-ray crystallography | transcription | actinobacteria | mycobacteria

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Section: Discussionmentioning

confidence: 49%

“…initiation complexes in vivo and stimulates transcription in vitro from a wide range of Sco σ HrdB -, Mtb σ A -, and Mtb σ B -dependent promoters (15,18), but the mechanism for RbpA-mediated transcription activation is unknown.…”

mentioning

confidence: 99%

Structural, functional, and genetic analyses of the actinobacterial transcription factor RbpA

Hubin

Tabib-Salazar

Humphrey

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Based on structural modeling, the RbpA BL domain and adjacent residues interact with the DNA phosphate backbone of the nontemplate strand upstream of the Ϫ10 promoter element in the RP o conformation (68). Additional contacts between RbpA and RNAP ␤ have been proposed based on cross-linking experiments (63, 73,74), but the recent structural modeling of RbpA onto an RNAP-promoter open complex would be incompatible with these interactions (71), suggesting that further analysis will be needed to resolve these inconsistencies. RbpA has been shown to increase the affinity of the factor to the core RNAP, increase the affinity of RNAP holoenzyme to promoter DNA, and facilitate the formation of RP o (71,75,76), all of which could contribute to the ability of RbpA to promote RNAP-promoter complex formation and stability.…”

Section: Factors: the Generals Of Stress Responsesmentioning

confidence: 99%

“…RbpA has been shown to increase the affinity of the factor to the core RNAP, increase the affinity of RNAP holoenzyme to promoter DNA, and facilitate the formation of RP o (71,75,76), all of which could contribute to the ability of RbpA to promote RNAP-promoter complex formation and stability. The housekeeping factor A has been reported to have an affinity for M. tuberculosis RNAP core enzyme similar to that of the alternative factor F (74), in which case RbpA may be necessary to improve A affinity and competitiveness for RNAP under conditions that require the activity of A . In E. coli, in contrast, 70 has a very high affinity to the RNAP core enzyme and thus can outcompete other factors under conditions where it is required without accessary factors such as RbpA.…”

Section: Factors: the Generals Of Stress Responsesmentioning

confidence: 99%

Mycobacterium tuberculosis Transcription Machinery: Ready To Respond to Host Attacks

2016

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Regulating responses to stress is critical for all bacteria, whether they are environmental, commensal, or pathogenic species. For pathogenic bacteria, successful colonization and survival in the host are dependent on adaptation to diverse conditions imposed by the host tissue architecture and the immune response. Once the bacterium senses a hostile environment, it must enact a change in physiology that contributes to the organism's survival strategy. Inappropriate responses have consequences; hence, the execution of the appropriate response is essential for survival of the bacterium in its niche. Stress responses are most often regulated at the level of gene expression and, more specifically, transcription. This minireview focuses on mechanisms of regulating transcription initiation that are required by Mycobacterium tuberculosis to respond to the arsenal of defenses imposed by the host during infection. In particular, we highlight how certain features of M. tuberculosis physiology allow this pathogen to respond swiftly and effectively to host defenses. By enacting highly integrated and coordinated gene expression changes in response to stress, M. tuberculosis is prepared for battle against the host defense and able to persist within the human population.T he survival of any organism relies on its ability to sense and respond to changes in its environment. For bacteria, stress responses are primarily mediated through the regulation of gene expression. By integrating multiple molecular approaches to gene regulation, pathogenic bacteria are able to orchestrate conditionspecific patterns that promote survival and pathogenesis in the face of a strong immune response. This minireview focuses on mechanisms of transcription regulation required for stress responses in one of the most successful and deadly pathogens in the world, Mycobacterium tuberculosis. M. tuberculosis has coexisted with humans for Ͼ50,000 years (1) and continues to cause more than 1.5 million deaths a year (2). The coevolution of M. tuberculosis with the human host response to infection has resulted in a pathogen that is specialized for long-term infection in people. Tuberculosis is a complex disease that requires the bacteria to multiply within phagocytes, survive extracellularly in hypoxic and necrotic granulomas, and endure a robust immune response to persist in the host. During infection, the host immune response restrains M. tuberculosis from proliferating by imposing a battery of defenses, including reactive oxygen and nitrogen stress, hypoxia, acid stress, genotoxic stress, cell surface stress, and starvation (3). Despite this onslaught of attacks, M. tuberculosis is able to persist for the lifetime of the host, indicating that this pathogen has highly effective molecular mechanisms to resist host-inflicted damage. In order to enact these defenses and facilitate this specialized lifestyle, M. tuberculosis executes a complex, interconnected web of stress responses that rely on changes in gene expression. In fact, M. tuberculosis is well suite...

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“…The essential transcription initiation factors CarD (Rv3583c) and RbpA (Rv2050) play important roles in the biology of M. tuberculosis. [39][40][41][42] Initiation requires the formation of RNA polymerase (RNAP) holoenzyme with the bound sigma factors. A series of kinetic steps bring about the formation of a closed complex leading to the open complex with the transcription bubble.…”

Section: Mycobacterium Tuberculosis: a Closer Lookmentioning

confidence: 99%

Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016

et al. 2016

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To say that tuberculosis (TB) has regained a strong foothold in the global human health and wellbeing scenario would be an understatement. Ranking alongside HIV/AIDS as the top reason for mortality due to a single infectious disease, the impact of TB extends far into socio-economic context worldwide. As global efforts led by experts and political bodies converge to mitigate the predicted outcome of growing antimicrobial resistance, the academic community of students, practitioners and researchers have mobilised to develop integrated, inter-disciplinary programmes to bring the plans of the former to fruition. Enabling this crucial requirement for unimpeded dissemination of scientific discovery was the TB Summit 2016, held in London, United Kingdom. This report critically discusses the recent breakthroughs made in diagnostics and treatment while bringing to light the major hurdles in the control of the disease as discussed in the course of the 3-day international event. Conferences and symposia such as these are the breeding grounds for successful local and global collaborations and therefore must be supported to expand the understanding and outreach of basic science research.

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Mycobacterium tuberculosis RbpA protein is a new type of transcriptional activator that stabilizes the σ A -containing RNA polymerase holoenzyme

Cited by 64 publications

References 51 publications

Structural, functional, and genetic analyses of the actinobacterial transcription factor RbpA

Structural, functional, and genetic analyses of the actinobacterial transcription factor RbpA

Mycobacterium tuberculosis Transcription Machinery: Ready To Respond to Host Attacks

Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016

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