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Here, we demonstrate that the MprBA-SigE\u2013SigB signaling pathway is activated in\n                      <jats:italic toggle=\"yes\">Mycobacterium smegmatis<\/jats:italic>\n                      under multiple stress conditions associated with respiratory inhibition, including genetic inactivation of the\n                      <jats:italic toggle=\"yes\">aa<\/jats:italic>\n                      <jats:sub>3<\/jats:sub>\n                      cytochrome\n                      <jats:italic toggle=\"yes\">c<\/jats:italic>\n                      oxidase, treatment with the\n                      <jats:italic toggle=\"yes\">bcc<\/jats:italic>\n                      <jats:sub>1<\/jats:sub>\n                      complex inhibitor Q203, hypoxia, high ionic strength, and acidic pH. Strikingly, acidic pH elicited the strongest activation of MprA-dependent\n                      <jats:italic toggle=\"yes\">sigE<\/jats:italic>\n                      expression, suggesting that MprB integrates multiple stress signals beyond respiratory dysfunction. Deletion of\n                      <jats:italic toggle=\"yes\">mprB<\/jats:italic>\n                      resulted in constitutive activation of MprA rather than inactivation, as evidenced by elevated\n                      <jats:italic toggle=\"yes\">sigE<\/jats:italic>\n                      expression, increased MprA phosphorylation, and enhanced rifampicin resistance in an\n                      <jats:italic toggle=\"yes\">mprB<\/jats:italic>\n                      mutant. Using CRISPRi-mediated repression and genetic deletion, we identified the KdpD histidine kinase, a component of the potassium homeostasis KdpDE TCS, as required for phosphorylating and activating MprA in the absence of MprB. These findings reveal unexpected crosstalk between KdpD and MprA. Expression of a truncated MprB lacking the N-terminal sensory domain abolished\n                      <jats:italic toggle=\"yes\">sigE<\/jats:italic>\n                      expression under both neutral and acidic conditions, indicating that this domain is essential for sensing environmental signals and that the truncated protein behaves as a phosphatase-dominant form under the conditions tested. Growth analysis revealed that MprA, SigE, and SigB are required for optimal growth under acidic conditions, demonstrating the importance of the MprBA-SigE\u2013SigB pathway for survival of\n                      <jats:italic toggle=\"yes\">M. smegmatis<\/jats:italic>\n                      under acidic stress.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The MprBA TCS contributes to mycobacterial stress adaptation and persistence by regulating SigE- and SigB-mediated stress response pathways. Here, we show that the MprBA TCS is activated under respiration-inhibitory and acidic conditions in\n                        <jats:italic toggle=\"yes\">Mycobacterium smegmatis<\/jats:italic>\n                        , suggesting that this pathway responds to environmental cues relevant to host infection. We also identify an unexpected regulatory relationship between the MprBA and KdpDE systems: in the absence of MprB, MprA can be phosphorylated and activated by the noncognate histidine kinase KdpD. These findings suggest that MprB phosphatase activity is critical for maintaining low basal MprA activity and preventing inappropriate KdpD-mediated activation under non-stress conditions.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jb.00361-26","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:37:25Z","timestamp":1791297445000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Activation of the MprBA two-component system in\n                    <i>Mycobacterium smegmatis<\/i>\n                    under acidic and respiration-inhibitory conditions and crosstalk between MprA and KdpD"],"prefix":"10.1128","author":[{"given":"Yun-Kyung","family":"Kim","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an57a31","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Integrated Biological Science, Pusan National University","place":["Busan, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye-Jin","family":"Lee","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an57a31","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Integrated Biological Science, Pusan National University","place":["Busan, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9250-2627","authenticated-orcid":true,"given":"Jeong-Il","family":"Oh","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an57a31","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Integrated Biological Science, Pusan National University","place":["Busan, South Korea"]},{"id":[{"id":"https:\/\/ror.org\/01an57a31","id-type":"ROR","asserted-by":"publisher"}],"name":"Microbiological Resource Research Institute, Pusan National University","place":["Busan, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221272198"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/31159"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.MGM2-0010-2013"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1872"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.12.6962-6970.2003"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01064-13"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.188.6.2134-2143.2006"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01167-09"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.187.1.202-212.2005"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00520-12"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.29281-0"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep43858"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05814.x"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001771"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSystems.00979-20"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.20.11554"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2006.02378.x"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1999.01212.x"},{"key":"e_1_3_3_20_2","first-page":"233","article-title":"Quantitative analysis of sigma genes expression in Mycobacterium tuberculosis cultures exposed to rifampicin and isoniazid","volume":"57","author":"Pendzich J","year":"2004","unstructured":"Pendzich J, Maksymowicz-Mazur W, Mazurek U, Dworniczak S, Oklek K, Kozielski J, Wilczok T. 2004. 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