DosS/DosR is a two-component regulatory system in which DosS, a heme-containing sensor also known as DevS, under certain conditions undergoes autophosphorylation and then transfers the phosphate to DosR, a DNA-binding protein that controls the entry of Mycobacterium tuberculosis and other mycobacteria into a latent, dormant state. DosT, a second sensor closely related to DosS, is present in M. tuberculosis and participates in the control of the dormancy response mediated by DosR. The binding of phosphorylated DosR to DNA initiates the expression of approximately fifty dormancy-linked genes. DosT is accepted to be a gas sensor that is activated in the ferrous state by the absence of an oxygen ligand or by the binding of NO or CO. DosS functions in a similar fashion as a gas sensor, but contradictory evidence has led to the suggestion that it also functions as a redox state sensor. This review focuses on the structure, biophysical properties, and function of the DosS/DosT heme sensors.
Voskuil, M.I.; Schnappinger, D.; Visconti, K.C.; Harrell, M.I.; Dolganov, G.M.; Sherman, D.R.; Schoolnik, G.K. Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J. Exp. Med. 2003, 198, 705–713, doi:10.1084/jem.20030205.
[3]
Betts, J.C.; Lukey, P.T.; Robb, L.C.; McAdam, R.A.; Duncan, K. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol. Microbiol. 2002, 43, 717–731, doi:10.1046/j.1365-2958.2002.02779.x.
[4]
Schnappinger, D.; Ehrt, S.; Voskuil, M.I.; Liu, Y.; Mangan, J.A.; Monahan, I.M.; Dolganov, G.; Efron, B.; Butcher, P.D.; Nathan, C.; Schoolnik, G.K. Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: Insights into the phagosomal environment. J. Exp. Med. 2003, 198, 693–704, doi:10.1084/jem.20030846.
[5]
Corbett, E.L.; Watt, C.J.; Walker, N.; Maher, D.; Williams, B.G.; Raviglione, M.C.; Dye, C. The growing burden of tuberculosis: Global trends and interactions with the HIV epidemic. Arch. Intern. Med. 2003, 163, 1009–1021, doi:10.1001/archinte.163.9.1009.
[6]
Flynn, J.L.; Chan, J.; Lin, P.L. Macrophages and control of granulomatous inflammation in tuberculosis. Mucosal Immunol. 2011, 4, 271–278, doi:10.1038/mi.2011.14.
[7]
Lim, A.; Eleuterio, M.; Hutter, B.; Murugasu-Oei, B.; Dick, T. Oxygen depletion induced dormancy in Mycobacterium bovis BCG. J. Bacteriol. 1999, 181, 2252–2256.
[8]
Sherman, D.R.; Voskuil, M.; Schnappinger, D.; Liao, R.; Harrell, M.I.; Schoolnik, G.K. Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha-crystallin. Proc. Natl. Acad. Sci. USA 2001, 98, 7534–7539.
[9]
Yuan, Y.; Crane, D.D.; Simpson, R.M.; Zhu, Y.Q.; Hickey, M.J.; Sherman, D.R.; Barry, C.E., III. The 16-kDa alpha-crystallin (Acr) protein of Mycobacterium tuberculosis is required for growth in macrophages. Proc. Natl. Acad. Sci. USA 1998, 95, 9578–9583.
[10]
Kinger, A.K.; Tyagi, J.S. Identification and cloning of genes differentially expressed in the virulent strain of Mycobacterium tuberculosis. Gene 1993, 131, 113–117, doi:10.1016/0378-1119(93)90678-V.
[11]
Dasgupta, N.; Kapur, V.; Singh, K.K.; Das, T.K.; Sachdeva, S.; Jyothisri, K.; Tyagi, J.S. Characterization of a two-component system, DevR-DevS, of Mycobacterium tuberculosis. Tuber. Lung Dis. 2000, 80, 141–159, doi:10.1054/tuld.2000.0240.
[12]
Saini, D.K.; Malhotra, V.; Dey, D.; Pant, N.; Das, T.K.; Tyagi, J.S. DevR-DevS is a bona fide two-component system of Mycobacterium tuberculosis that is hypoxia-responsive in the absence of the DNA-binding domain of DevR. Microbiology 2004, 150, 865–875, doi:10.1099/mic.0.26218-0.
[13]
Roberts, D.M.; Liao, R.P.; Wisedchaisri, G.; Hol, W.G.J.; Sherman, D.R. Two sensor kinases contribute to the hypoxic response of Mycobacterium tuberculosis.. J. Biol. Chem. 2004, 279, 23082–23087.
[14]
Muttucumaru, D.G.N.; Roberts, G.; Hinds, J.; Stabler, R.A.; Parish, T. Gene expression profile of Mycobacterium tuberculosis in a non-replicating state. Tuberculosis 2004, 84, 239–246, doi:10.1016/j.tube.2003.12.006.
Honaker, R.W.; Leistikow, R.L.; Bartek, I.L.; Voskuil, M.I. Unique roles of DosT and DosS in DosR regulon induction and Mycobacterium tuberculosis dormancy. Infect. Immun. 2009, 77, 3258–4363, doi:10.1128/IAI.01449-08.
[17]
Boon, C.; Li, R.; Qi, R.; Dick, T. Proteins of Mycobacterium bovis BCG induced in the Wayne dormancy model. J. Bacteriol. 2001, 183, 2672–2676, doi:10.1128/JB.183.8.2672-2676.2001.
[18]
Boon, C.; Dick, T. Mycobacterium bovis BCG response regulator essential for hypoxic dormancy. J. Bacteriol. 2002, 184, 6760–6767, doi:10.1128/JB.184.24.6760-6767.2002.
[19]
Malhotra, V.; Sharma, D.; Ramanathan, V.D.; Shakila, H.; Saini, D.K.; Chakravorty, S.; Das, T.K.; Li, Q.; Silver, R.F.; Narayanan, P.R.; Tyagi, J.S. Disruption of response regulator gene, devR, leads to attenuation in virulence of Mycobacterium tuberculosis. FEMS Microbiol. Lett. 2004, 231, 237–245, doi:10.1016/S0378-1097(04)00002-3.
[20]
Rustad, T.R.; Harrell, M.I.; Liao, R.; Sherman, D.R. The enduring hypoxic response of Mycobacterium tuberculosis. PLoS ONE 2008, 1, e1502, doi:10.1371/journal.pone.0001502.
[21]
Converse, P.J.; Karakousis, P.C.; Klinkenberg, L.G.; Kesavan, A.K.; Ly, L.H.; Allen, S.S.; Grosset, J.H.; Jain, S.K.; Lamichhane, G.; Manabe, Y.C.; McMurray, D.N.; Nuermberger, E.L.; Bishai, W.R. Role of the dosR-dosS two-component regulatory system in Mycobacterium tuberculosis virulence in three animal models. Infect. Immun. 2009, 77, 1230–1237, doi:10.1128/IAI.01117-08.
[22]
Parish, T.; Smith, D.A.; Kendall, S.; Casali, N.; Bancroft, G.J.; Stoker, N.G. Deletion of two-component regulatory systems increases the virulence of Mycobacterium tuberculosis. Infect. Immun. 2003, 71, 1134–1140, doi:10.1128/IAI.71.3.1134-1140.2003.
[23]
Mayuri, G.B.; Das, T.K.; Tyagi, J.S. Molecular analysis of the dormancy response in Mycobacterium smegmatis: Expression analysis of genes encoding the DevR-DevS two-component system, Rv3134c and chaperone a-crystallin homologues. FEMS Microbiol. Lett. 2002, 211, 231–237.
[24]
Kim, M.-J.; Park, K.-J.; Ko, I.-J.; Kim, Y.M.; Oh, J.-I. Different roles of DosS and DosT in the hypoxic adaptation of mycobacteria. J. Bacteriol. 2010, 192, 4868–4875.
[25]
Lee, J.-M.; Cho, H.Y.; Cho, H.J.; Park, S.W.; Baik, H.-S.; Oh, J.-H.; Eom, C.-Y.; Kim, Y.M.; Kang, B.S.; Oh, J.-I. O2？ and NO-sensing mechanism through the DevSR two-component system of Mycobacterium smegmatis. J. Bacteriol. 2008, 190, 6795–6804, doi:10.1128/JB.00401-08.
[26]
Park, H.-D.; Guinn, K.M.; Harrell, M.I.; Liao, R.; Voskuil, M.I.; Tompa, M.; Schoolnik, G.K.; Sherman, D.R. Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis. Mol. Microbiol. 2003, 48, 833–843, doi:10.1046/j.1365-2958.2003.03474.x.
[27]
Saini, D.K.; Malhotra, V.; Tyagi, J.S. Cross talk between DevS sensor kinase homologue, Rv2027c, and DevR response regulator of Mycobacterium tuberculosis. FEBS Lett. 2004, 565, 75–80, doi:10.1016/j.febslet.2004.02.092.
[28]
Sardiwal, S.; Kendall, S.L.; Movahedzadeh, F.; Rison, S.C.G.; Stoker, N.G.; Djordjevic, S. A GAF domain in the hypoxia/NO-inducible Mycobacterium tuberculosis DosS protein binds haem. J. Mol. Biol. 2005, 353, 929–936, doi:10.1016/j.jmb.2005.09.011.
[29]
Saini, D.K.; Pant, N.; Das, T.K.; Tyagi, J.S. Cloning, overexpression, purification, and matris-assisted refolding of devS (Rv 3132c) histidine protein kinase of Mycobacterium tuberculosis. Protein Expres. Purif. 2002, 25, 203–208, doi:10.1006/prep.2002.1628.
[30]
Ioanoviciu, A.; Yukl, E.T.; Mo？nne-Loccoz, P.; Ortiz de Montellano, P.R. DevS, a heme-containing two-component oxygen sensor of Mycobacterium tuberculosis. Biochemistry 2007, 46, 4250–4260, doi:10.1021/bi602422p.
[31]
Yukl, E.T.; Ioanoviciu, A.; Ortiz de Montellano, P.R.; Mo？nne-Loccoz, P. Interdomain interactions within the two-component heme-based sensor protein DevS from Mycobacterium tuberculosis. Biochemistry 2007, 46, 9728–9736.
[32]
Podust, L.M.; Ioanoviciu, A.; Ortiz de Montellano, P.R. 2.3 ？ X-ray structure of the heme-bound GAF domain of sensory histidine kinase DosT of Mycobacterium tuberculosis. Biochemistry 2008, 47, 12523–12531, doi:10.1021/bi8012356.
[33]
Sousa, E.H.S.; Tuckerman, J.R.; Gonzalez, G.; Gilles-Gonzalez, M.-A. DosT and DevS are oxygen-switched kinases in Mycobacterium tuberculosis. Protein Sci. 2007, 16, 1708–1719, doi:10.1110/ps.072897707.
[34]
Kumar, A.; Toledo, J.C.; Patel, R.P.; Lancaster, J.R., Jr.; Steyn, A.J. Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor. Proc. Natl. Acad. Sci. USA 2007, 104, 11568–11573, doi:10.1073/pnas.0705054104.
[35]
Cho, H.Y.; Cho, H.J.; Kim, Y.M.; Oh, J.I.; Kang, B.S. Structural insight into the heme-based redox sensing by DosS from Mycobacterium tuberculosis. J. Biol. Chem. 2009, 284, 13057–13067.
[36]
Cho, H.Y.; Cho, H.J.; Kim, M.H.; Kang, B.S. Blockage of the channel to heme by the E87 side chain in the GAF domain of Mycobacterium tuberculosis DosS confers the unique sensitivity of DosS to oxygen. FEBS Lett. 2011, 585, 1873–1878, doi:10.1016/j.febslet.2011.04.050.
[37]
Yukl, E.T.; Ioanoviciu, A.; Nakano, M.M.; Ortiz de Montellano, P.R.; Mo？nne-Loccoz, P. A distal tyrosine residue is required for ligand discrimination in DevS from Mycobacterium tuberculosis. Biochemistry 2008, 47, 12532–12539, doi:10.1021/bi801234w.
[38]
Ioanoviciu, A.; Meharenna, Y.T.; Poulos, T.L.; Ortiz de Montellano, P.R. DevS oxy complex stability identifies this heme protein as a gas sensor in Mycobacterium tuberculosis dormancy. Biochemistry 2009, 48, 5839–5848, doi:10.1021/bi802309y.
[39]
Cho, H.Y.; Lee, Y.-H.; Bae, Y.-S.; Kim, E.; Kang, B.S. Activation of ATP binding for the autophosphorylation of DosS, a Mycobacterium tuberculosis histidine kinase lacking an ATP-lid motif. J. Biol. Chem. 2013, 288, 12437–12447, doi:10.1074/jbc.M112.442467.
[40]
Nowak, E.; Panjikar, S.; Morth, J.P.; Jordanova, R.; Svergun, D.I.; Tucker, P.A. Structural and functional aspects of the sensor histidine kinase PrrB from Mycobacterium tuberculosis. Structure 2006, 14, 275–285, doi:10.1016/j.str.2005.10.006.
[41]
Casino, P.; Rubio, V.; Marina, A. Structural insight into partner specificity and phosphoryl transfer in two-component signal transduction. Cell 2009, 139, 325–336, doi:10.1016/j.cell.2009.08.032.
[42]
Sherman, D.R.; Voskuil, M.; Schnappinger, D.; Liao, R.; Harrell, M.I.; Schoolnik, G.K. Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding a-crystallin. Proc. Natl. Acad. Sci. USA 2001, 98, 7534–7539.
[43]
Honaker, R.W.; Dhiman, R.K.; Narayanasamy, P.; Crick, D.C.; Voskuil, M.I. DosS responds to a reduced electron transport system to induce the Mycobacterium tuberculosis DosR regulon. J. Bacteriol. 2010, 192, 6447–6455, doi:10.1128/JB.00978-10.
[44]
Taneja, N.K.; Dhingra, S.; Mittal, A.; Naresh, M.; Tyagi, J.S. Mycobacterium tuberculosis transcriptional adaptation, growth arrest, and dormancy phenotype development is triggered by vitamin C. PLoS ONE 2010, 5, e10860, doi:10.1371/journal.pone.0010860.
[45]
Yukl, E.T.; Ioanoviciu, A.; Sivaramakrishnan, S.; Nakano, M.M.; Ortiz de Montellano, P.R.; Mo？nne-Loccoz, P. Nitric oxide dioxygenation reaction in DevS and the initial response to nitric oxide in Mycobacterium tuberculosis. Biochemistry 2011, 50, 1023–1028.
[46]
Lee, H.-N.; Lee, N.-O.; Ko, I.-J.; Kim, S.W.; Kang, B.S.; Oh, J.-I. Involvement of the catalytically important Asp54 residue of Mycobacterium smegmatis DevR in protein-protein interactions between DevR and DevS. FEMS Microbiol Lett. 2013, 343, 26–33, doi:10.1111/1574-6968.12122.
[47]
Leistikow, R.L.; Morton, R.A.; Barteck, I.L.; Frimpong, I.; Wagner, K.; Voskuil, M.I. The Mycobacterium tuberculosis DosR regulon assists in metabolic homeostasis and enables rapid recovery from nonrespiring dormancy. J. Bacteriol. 2010, 192, 1662–1670, doi:10.1128/JB.00926-09.
[48]
Kendall, S.L.; Movahedzadeh, F.; Rison, S.C.G.; Wernbisch, L.; Parish, T.; Duncan, K.; Betts, J.C.; Stoker, N.G. The Mycobacterium tuberculosis dosRS two-component system is induced by multiple stresses. Tuberculosis 2004, 84, 247–255, doi:10.1016/j.tube.2003.12.007.
[49]
Parish, T.; Smith, D.A.; Kendall, S.; Casali, N.; Bancroft, G.J.; Stoker, N.G. Deletion of two-component regulatory systems increases the virulence of Mycobacterium tuberculosis. Infect. Immun. 2003, 71, 1134–1140, doi:10.1128/IAI.71.3.1134-1140.2003.
[50]
Nambu, S.; Matsui, T.; Goulding, C.W.; Takahashi, S.; Ikeda-Saito, M. A new way to degrade heme: The Mycobacterium tuberculosis enzyme MhuD catalyzes heme degradation without generating CO. J. Biol. Chem. 2003, 288, 10101–10109.
[51]
Vos, M.H.; Bouzhir-Sima, L.; Lambry, J.-C.; Luo, H.; Eaton-Rye, J.J.; Ionaoviciu, A.; Ortiz de Montellano, P.R.; Liebl, U. Ultrafast ligand dynamics in the heme-based GAF sensor domains of the histidine kinases DosS and DosT from Mycobacterium tuberculosis. Biochemistry 2012, 51, 159–166.
[52]
Matsoso, L.G.; Kana, B.D.; Crellin, P.K.; Lea-Smith, D.J.; Pelosi, A.; Powell, D.; Dawes, S.S.; Rubin, H.; Coppel, R.L.; Mizrahi, V. Function of the cytochrome bc1-aa3 branch of the respiratory network in mycobacteria and network adaptation occurring in response to its disruption. J. Bacteriol. 2005, 187, 6300–6308, doi:10.1128/JB.187.18.6300-6308.2005.
[53]
Singh, A.; Mai, D.; Kumar, A.; Steyn, A.J.C. Dissecting virulence pathways of Mycobacterium tuberculosis through protein-protein association. Proc. Natl. Acad. Sci. USA 2006, 103, 11346–11351, doi:10.1073/pnas.0602817103.
[54]
Bagchi, G.; Chauhan, S.; Sharma, D.; Tyagi, J.S. Transcription and autoregulation of the Rv3134c-devR-devS operon in Mycobacterium tuberculosis. Microbiology 2005, 151, 4045–4053, doi:10.1099/mic.0.28333-0.
[55]
Chauhan, S.; Tyagi, J.S. Cooperative binding of phosphorylated DevR to upstream sites is necessary and sufficient for activation of Rv3134c-devRS operon in Mycobacterium tuberculosis: Implication in the induction of devR target genes. J. Bacteriol. 2008, 190, 4301–4312, doi:10.1128/JB.01308-07.
[56]
Chauhan, S.; Tyagi, J.S. Interaction of DevR with multiple binding sites synergistically activates divergent transcription of narK2-Rv1738 genes in Mycobacterium tuberculosis. J. Bacteriol. 2008, 190, 5394–5403, doi:10.1128/JB.00488-08.
[57]
Gautam, U.S.; Sikri, K.; Tyagi, J.S. The residue threonine 82 of DevR (DosR) is essential for DevR activation and function in Mycobacterium tuberculosis despite its atypical location. J. Bacteriol. 2011, 193, 4849–4858, doi:10.1128/JB.05051-11.
[58]
Gautam, U.S.; Chauhan, S.; Tyagi, J.S. Determinants outside of the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis. PLoS ONE 2011, 6, e16500, doi:10.1371/journal.pone.0016500.
[59]
Wisedchaisri, G.; Wu, M.; Sherman, D.R.; Hol, W.G.J. Crystal structures of the response regulator DosR from Mycobacterium tuberculosis suggest a helix rearrangement mechanism for phosphorylation activation. J. Mol. Biol. 2008, 378, 227–242, doi:10.1016/j.jmb.2008.02.029.
[60]
Wesidchaisri, G.; Wu, M.; Rice, A.E.; Roberts, D.M.; Sherman, D.R.; Hol, W.G.J. Structures of Mycobacterium tuberculosis DosR and DosR-DNA complex involved in gene activation during adaptation to hypoxic latency. J. Mol. Biol. 2005, 354, 630–641.
[61]
Saini, D.K.; Tyagi, J.S. High-throughput microplate phosphorylation assays based on DevR-DevS/Rv2027c 2-component signal transduction pathway to screen for novel antitubercular compounds. J. Biomolec. Screening 2005, 10, 215–224, doi:10.1177/1087057104272090.
[62]
Gupta, R.K.; Thakur, T.S.; Deriraju, G.R.; Tyagi, J.S. Structure-based design of DevR inhibitor active against nonreplicating Mycobacterium tuberculosis. J. Med. Chem. 2009, 52, 6324–6334.
