Insight into the Dual Functions of Bacterial Enhancer-Binding Protein Rrp2 of Borrelia burgdorferi

Yin, Yanping; Yang, Youyun; Xiang, Xuwu; Wang, Qian; Zhang, Yang; Blevins, Jon S.; Lou, Yongliang; Yang, Xiaofeng

doi:10.1128/jb.01010-15

Cited by 13 publications

(11 citation statements)

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“…We and others showed that Rrp2 phosphorylation is required for cell growth, in addition to activation of σ 54 -σ S cascade (34,35). If HK2 overexpression reduces the level of Rrp2 phosphorylation, one would expect that it will affect spirochetal growth.…”

Section: Hk2 Functions As a Phosphatase Of Rrp2mentioning

confidence: 90%

Role of HK2 in the Enzootic Cycle of Borrelia burgdorferi

Liu

Zhang

et al. 2020

Front. Med.

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The two-component response regulator Rrp2 is a key activator controlling the production of numerous virulence factors of Borrelia burgdorferi, the Lyme disease pathogen. Previously it was shown that the cognate histidine kinase HK2 is not required for Rrp2 activation in vitro, nor for mammalian infection upon needle inoculation, raising the question whether HK2 has any role in the enzootic cycle of B. burgdorferi. In this study, we demonstrated that HK2 is not required for spirochetal survival in the tick vector. When fed on naive mice, the hk2 mutant had reduced infectivity through the route of tick bite, suggesting that the spirochetes lacking HK2 had a disadvantage in the enzootic cycle. Furthermore, overexpression of hk2 reduced the level of Rrp2 phosphorylation, suggesting that HK2 can function as a phosphatase to dephosphorylate Rrp2. Strains overexpressing hk2 impaired the expression of RpoN regulon whose activation is dependent on Rrp2 phosphorylation and activation, and had reduced infectivity in mice. Taken together, these results demonstrate that although HK2 does not play an essential role in Rrp2 activation, it is important for the optimal fitness of B. burgdorferi in the enzootic cycle.

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Section: Hk2 Functions As a Phosphatase Of Rrp2mentioning

confidence: 90%

Role of HK2 in the Enzootic Cycle of Borrelia burgdorferi

Liu

Zhang

et al. 2020

Front. Med.

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“…Compared with the other two structural domains (i.e., R and D), the central C domain is highly conserved among bEBPs (Studholme and Dixon, ; Rappas et al ., ; Wigneshweraraj et al ., ; Bush and Dixon, ). Moreover, previous studies have indicated that the G239 residue in Rrp2's C domain could readily be mutated in B. burgdorferi (Yang et al ., ; Boardman et al ., ; Ouyang et al ., ; Blevins et al ., ; Groshong et al ., ; Yin et al ., ). Of note, the residue G239 is located just upstream of the Walker B motif (positions 240‐245) in Rrp2's C domain (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…Furthermore, many structural and biochemical studies (Morett and Segovia, 1993;Osuna et al, 1997;Pelton et al, 1999;Ray et al, 2005;Sallai and Tucker, 2005;Rappas et al, 2006Rappas et al, , 2007Batchelor et al, 2008;Wigneshweraraj et al, 2008;Bush and Dixon, 2012) have indicated that nucleotide binding and hydrolysis cause significant conformational changes of bEBPs, which is directly linked to the activation of r 54 -dependent genes. Despite that Rrp2's D domain has been suggested to be dispensable for the activation of r 54dependent rpoS transcription (Burtnick et al, 2007;Blevins et al, 2009), one recent study reported that Rrp2's D domain, as well as its R domain, is required for spirochetal growth (Yin et al, 2016); Rrp2 variants with the D domain or R domain truncated were incapable of supporting borrelial growth in BSK medium. Our study here adds that Rrp2's ATPase activity also is required for borrelial viability and the regulation over r 54 /RpoS-independent essential genes.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, rrp2 conditional lethal mutations were created by three different groups (Groshong et al, 2012;Ouyang et al, 2014;Yin et al, 2016). All of those three conditional rrp2 mutants were merodiploid strains, in which Rrp2 was expressed from a shuttle vector carrying PpQE30-rrp2.…”

Section: Generation Of An Rrp2 Conditional Mutant In B Burgdorferimentioning

confidence: 99%

“…To date, it has not been possible to eliminate Rrp2 from B. burgdorferi ; all efforts to obtain a null rrp2 mutant in B. burgdorferi have been unsuccessful, suggesting that Rrp2 is essential for borrelial growth. This hypothesis was confirmed recently; by exploiting rrp2 conditional mutants, we (Ouyang et al ., ) and others (Groshong et al ., ; Yin et al ., ) found that abolishment of Rrp2 is lethal for B. burgdorferi growth in BSK medium. These more recent data imply that Rrp2 may activate or repress other as yet uncharacterized σ 54 /RpoS‐independent genes essential for borrelial replication in vitro , because mutations in rpoN and rpoS are not lethal for the growth of the spirochete (Hubner et al ., ; Caimano et al ., ; Fisher et al ., ; Ouyang et al ., ; Dunham‐Ems et al ., ).…”

Section: Introductionmentioning

confidence: 99%

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The putative Walker A and Walker B motifs of Rrp2 are required for the growth of Borrelia burgdorferi

Ouyang

Zhou

2016

Molecular Microbiology

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SummaryRrp2 encodes a putative bacterial enhancer binding protein (bEBP) in Borrelia burgdorferi. Point mutation (G239C) of Rrp2 abolishes the transcriptional activation of r 54 -dependent rpoS. In contrast to canonical bEBPs that are dispensable for bacterial growth, Rrp2 is essential for borrelial growth in BSK medium. It has been believed that Rrp2's ATPase activity is not required for cell growth, but experimental evidence supporting this notion has been lacking. In particular, it has remained unclear whether the residue G239 is involved in Rrp2's presumptive ATPase activity. To address these information gaps, we examined the roles of Rrp2's potential strategic signatures including the G239 residue and the putative Walker A and Walker B motifs. Herein it was showed that Rrp2 has ATP binding and hydrolysis activities engendered by the Walker A and B motifs respectively. However, these activities were not significantly impaired by a G239C mutation. Further mutagenesis analyses indicated that Rrp2's Walker A and B motifs are required for borrelial growth; mutations of key residues in these two motifs were lethal to B. burgdorferi. The combined data suggest that the Walker A and Walker B motifs of Rrp2 are involved in the control of another unknown RpoS-independent gene product(s) associated with borrelial replication.

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Regulation of Gene and Protein Expression in the Lyme Disease Spirochete

Stevenson

Seshu

2017

Current Topics in Microbiology and Immunology

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The infectious cycle of Borrelia burgdorferi necessitates persistent infection of both vertebrates and ticks, and efficient means of transmission between those two very different types of hosts. The Lyme disease spirochete has evolved mechanisms to sense its location in the infectious cycle, and use that information to control production of the proteins and other factors required for each step. Numerous components of borrelial regulatory pathways have been characterized to date. Their effects are being pieced together, thereby providing glimpses into a complex web of cooperative and antagonistic interactions. In this chapter, we present a broad overview of B. burgdorferi gene and protein regulation during the natural infectious cycle, discussions of culture-based methods for elucidating regulatory mechanisms, and summaries of many of the known regulatory proteins and small molecules. We also highlight areas that are in need of substantially more research.

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Insight into the Dual Functions of Bacterial Enhancer-Binding Protein Rrp2 of Borrelia burgdorferi

Abstract: It is well established that the

Cited by 13 publications

References 40 publications

Role of HK2 in the Enzootic Cycle of Borrelia burgdorferi

Role of HK2 in the Enzootic Cycle of Borrelia burgdorferi

The putative Walker A and Walker B motifs of Rrp2 are required for the growth of Borrelia burgdorferi

Regulation of Gene and Protein Expression in the Lyme Disease Spirochete

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