{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T18:08:11Z","timestamp":1781201291779,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.pgen.1012202","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000}}],"reference-count":86,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 AI143768 and R21 AI168597"],"award-info":[{"award-number":["R01 AI143768 and R21 AI168597"]}]},{"DOI":"10.13039\/100009578","name":"Mizutani Foundation for Glycoscience","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009578","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008975","name":"University of Massachusetts Amherst","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008975","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["T32 GM007310"],"award-info":[{"award-number":["T32 GM007310"]}]},{"DOI":"10.13039\/100008090","name":"Tufts University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008975","name":"University of Massachusetts Amherst","doi-asserted-by":"publisher","award":["T32 GM139789"],"award-info":[{"award-number":["T32 GM139789"]}],"id":[{"id":"10.13039\/100008975","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    During infection,\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (Mtb) encounters multiple environmental stressors, including nitric oxide (NO) and iron limitation, and an ability to mount an integrated response is essential for the bacterium\u2019s adaptation and continued survival. Iron-containing prosthetic groups in key enzymes are critical for Mtb sensing and detoxification of NO, and there is significant overlap between NO- and low iron-responsive genes. However, how Mtb adapts to these two stressors concurrently is largely unknown. Here, we find that exposure to NO globally augments expression of low iron-responsive genes and vice versa, with a two gene operon,\n                    <jats:italic>rv3839-rv3840,<\/jats:italic>\n                    among the most highly upregulated. Deletion of\n                    <jats:italic>rv3839-rv3840<\/jats:italic>\n                    resulted in increased growth under prolonged iron limitation and early exit of Mtb from an adaptive state of growth arrest induced upon exposure to NO\/low iron. \u2206\n                    <jats:italic>rv3839-rv3840<\/jats:italic>\n                    Mtb exhibited an elongated cell morphology compared to wild type Mtb in NO\/low iron conditions, indicating effects of this operon on cell growth and division under stress conditions, with Rv3839 as the key driver of this phenotype. Coproporphyrin III tetramethyl ester (TMC), a modified precursor molecule in the endogenous Mtb heme biosynthesis pathway, was found to accumulate in \u2206\n                    <jats:italic>rv3839-rv3840<\/jats:italic>\n                    Mtb under iron limiting conditions. Further, intrabacterial heme levels were increased in \u2206\n                    <jats:italic>rv3839-rv3840<\/jats:italic>\n                    Mtb under NO stress and iron limitation. Together, these findings reveal Rv3839-Rv3840 as proteins involved in the downregulation of heme biosynthesis under NO stress and iron limitation, and highlight the link between Mtb growth control in response to NO\/low iron and endogenous heme biosynthesis.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1012202","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T17:44:21Z","timestamp":1780940661000},"page":"e1012202","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rv3839-Rv3840 links the endogenous heme biosynthesis pathway with Mycobacterium tuberculosis adaptation to nitric oxide and iron limitation stress"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0173-4332","authenticated-orcid":true,"given":"Natalia 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