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HipB DNA-binding transcriptional repressor

Synonyms: HipB
HipB is a transcriptional repressor that functions as the antagonist of HipA, which was the first protein found to mediate the phenomenon of persistence in E. coli. A small fraction of cells within a population are dormant persister cells; these cells are phenotypic variants that are not killed by antibiotics, leading to multidrug tolerance (MDT). Persistence may be ultimately due to global remodeling of the persister cell's ribosomes [3]. The HipAB system can be categorized as a type II toxin/antitoxin module. In the absence of its binding partner HipB, HipA is toxic to the cell [2, 4, 5]. Above a certain threshold, the level of HipA in the cell determines the typical duration of growth arrest. The threshold level is determined by the level of HipB [5]. The HipAB system appears to be regulated at the level of HipB stability. Degradation of HipB is mainly dependent on the Lon protease, and is dependent on an unstructured 16 amino acid domain at the C terminus of the protein [6]. A variety of crystal structures of HipB in complexes with DNA and HipA have been solved [7, 8, 9, 10].
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Transcription factor      
TF conformation(s):
Name Conformation Type TF-Effector Interaction Type Apo/Holo Conformation Evidence (Confirmed, Strong, Weak) References
HipB Functional   nd nd
Evolutionary Family: HTH_3
Connectivity class: Local Regulator
Gene name: hipB
  Genome position: 1592176-1592442
  Length: 267 bp / 88 aa
Operon name: hipBA
TU(s) encoding the TF:
Transcription unit        Promoter

Regulated gene(s) fadH, hipA, hipB, mazE, mazF, relA
Multifun term(s) of regulated gene(s) MultiFun Term (List of genes associated to the multifun term)
translation (2)
defense/survival (2)
starvation (2)
other (mechanical, nutritional, oxidative stress) (2)
cell killing (2)
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Regulated operon(s) fadH, hipBA, relA-mazEFG
First gene in the operon(s) fadH, hipB, relA
Simple and complex regulons ArcA,CRP,FadR,HipB
Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)

Transcription factor regulation    

Transcription factor binding sites (TFBSs) arrangements

  Functional conformation Function Promoter Sigma factor Central Rel-Pos Distance to first Gene Genes Sequence LeftPos RightPos Evidence (Confirmed, Strong, Weak) References
  HipB repressor fadHp nd -132.5 -173.5 fadH
3231474 3231510 [GEA], [APIORCISFBSCS], [BPP] [1]
  HipB repressor hipBp Sigma70 -85.5 -125.5 hipB, hipA
1592558 1592577 [GEA], [APIORCISFBSCS], [BPP] [2]
  HipB repressor hipBp Sigma70 -57.5 -97.5 hipB, hipA
1592530 1592549 [GEA], [APIORCISFBSCS], [BPP] [2]
  HipB repressor hipBp Sigma70 -18.5 -58.5 hipB, hipA
1592491 1592511 [GEA], [APIORCISFBSCS], [BPP] [2]
  HipB repressor hipBp Sigma70 10.5 -30.5 hipB, hipA
1592463 1592482 [GEA], [APIORCISFBSCS], [BPP] [2]
  HipB repressor relAp1 Sigma70 5.0 -174.0 relA, mazE, mazF
2913809 2913842 [GEA], [BPP] [1]

High-throughput Transcription factor binding sites (TFBSs)

  Functional conformation Function Object name Object type Distance to first Gene Sequence LeftPos RightPos Center Position Growth Condition Evidence (Confirmed, Strong, Weak) References
  HipB repressor eutHA Transcription-Unit -171.5
2568261 2568297 2568278.5 nd [GEA], [APIORCISFBSCS], [BPP] [1]
  HipB repressor eutHA Transcription-Unit -71.5
2568161 2568197 2568178.5 nd [GEA], [AIBSCS], [BPP] [1]

Evolutionary conservation of regulatory elements    
     Note: Evolutionary conservation of regulatory interactions and promoters is limited to gammaproteobacteria.
TF-target gene evolutionary conservation
Promoter-target gene evolutionary conservation


 [1] Lin CY., Awano N., Masuda H., Park JH., Inouye M., 2013, Transcriptional repressor HipB regulates the multiple promoters in Escherichia coli., J Mol Microbiol Biotechnol 23(6):440-7

 [2] Black DS., Irwin B., Moyed HS., 1994, Autoregulation of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis., J Bacteriol 176(13):4081-91

 [3] Cho J, Rogers J, Kearns M, Leslie M, Hartson SD, Wilson KS, 2015, Escherichia coli persister cells suppress translation by selectively disassembling and degrading their ribosomes., Mol Microbiol, 95(2):352 10.1111/mmi.12884

 [4] Black DS., Kelly AJ., Mardis MJ., Moyed HS., 1991, Structure and organization of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis., J Bacteriol 173(18):5732-9

 [5] Rotem E, Loinger A, Ronin I, Levin-Reisman I, Gabay C, Shoresh N, Biham O, Balaban NQ, 2010, Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence., Proc Natl Acad Sci U S A, 107(28):12541 10.1073/pnas.1004333107

 [6] Hansen S, Vuli? M, Min J, Yen TJ, Schumacher MA, Brennan RG, Lewis K, 2012, Regulation of the Escherichia coli HipBA toxin-antitoxin system by proteolysis., PLoS One, 7(6):e39185 10.1371/journal.pone.0039185

 [7] Schumacher MA, Piro KM, Xu W, Hansen S, Lewis K, Brennan RG, 2009, Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB., Science, 323(5912):396 10.1126/science.1163806

 [8] Evdokimov A, Voznesensky I, Fennell K, Anderson M, Smith JF, Fisher DA, 2009, New kinase regulation mechanism found in HipBA: a bacterial persistence switch., Acta Crystallogr D Biol Crystallogr, 65(Pt 8):875 10.1107/S0907444909018800

 [9] Schumacher MA, Min J, Link TM, Guan Z, Xu W, Ahn YH, Soderblom EJ, Kurie JM, Evdokimov A, Moseley MA, Lewis K, Brennan RG, 2012, Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance., Cell Rep, 2(3):518 10.1016/j.celrep.2012.08.013

 [10] Schumacher MA, Balani P, Min J, Chinnam NB, Hansen S, Vuli? M, Lewis K, Brennan RG, 2015, HipBA-promoter structures reveal the basis of heritable multidrug tolerance., Nature, 524(7563):59 10.1038/nature14662

 [11] Balaban NQ, Merrin J, Chait R, Kowalik L, Leibler S, 2004, Bacterial persistence as a phenotypic switch., Science, 305(5690):1622 10.1126/science.1099390

 [12] Lou C, Li Z, Ouyang Q, 2008, A molecular model for persister in E. coli., J Theor Biol, 255(2):205 10.1016/j.jtbi.2008.07.035

 [13] Koh RS, Dunlop MJ, 2012, Modeling suggests that gene circuit architecture controls phenotypic variability in a bacterial persistence network., BMC Syst Biol, 6(None):47 10.1186/1752-0509-6-47

 [14] Feng J, Kessler DA, Ben-Jacob E, Levine H, 2014, Growth feedback as a basis for persister bistability., Proc Natl Acad Sci U S A, 111(1):544 10.1073/pnas.1320396110

 [15] Keren I, Shah D, Spoering A, Kaldalu N, Lewis K, 2004, Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli., J Bacteriol, 186(24):8172 10.1128/JB.186.24.8172-8180.2004

 [16] Zhao J, Wang Q, Li M, Heijstra BD, Wang S, Liang Q, Qi Q, 2013, Escherichia coli toxin gene hipA affects biofilm formation and DNA release., Microbiology (Reading), 159(Pt 3):633 10.1099/mic.0.063784-0

 [17] Korch SB, Hill TM, 2006, Ectopic overexpression of wild-type and mutant hipA genes in Escherichia coli: effects on macromolecular synthesis and persister formation., J Bacteriol, 188(11):3826 10.1128/JB.01740-05

 [18] Moyed HS, Bertrand KP, 1983, hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis., J Bacteriol, 155(2):768 10.1128/jb.155.2.768-775.1983

 [19] Maisonneuve E, Gerdes K, 2014, Molecular mechanisms underlying bacterial persisters., Cell, 157(3):539 10.1016/j.cell.2014.02.050

 [20] Kåhrström CT, 2013, Bacterial physiology: a persistent magic spot., Nat Rev Microbiol, 11(11):739 10.1038/nrmicro3134

 [21] Brzozowska I, Zielenkiewicz U, 2013, Regulation of toxin-antitoxin systems by proteolysis., Plasmid, 70(1):33 10.1016/j.plasmid.2013.01.007

 [22] Yamaguchi Y, Park JH, Inouye M, 2011, Toxin-antitoxin systems in bacteria and archaea., Annu Rev Genet, 45(None):61 10.1146/annurev-genet-110410-132412

 [23] Lewis K, 2008, Multidrug tolerance of biofilms and persister cells., Curr Top Microbiol Immunol, 322(None):107 10.1007/978-3-540-75418-3_6

 [24] Jayaraman R, 2008, Bacterial persistence: some new insights into an old phenomenon., J Biosci, 33(5):795 10.1007/s12038-008-0099-3

 [25] Lewis K, 2007, Persister cells, dormancy and infectious disease., Nat Rev Microbiol, 5(1):48 10.1038/nrmicro1557

 [26] Lewis K, 2005, Persister cells and the riddle of biofilm survival., Biochemistry (Mosc), 70(2):267 10.1007/s10541-005-0111-6