{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:04:53Z","timestamp":1782281093855,"version":"3.54.5"},"posted":{"date-parts":[[2026,2,4]]},"group-title":"Microbiology","reference-count":92,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  During infection, pathogenic mycobacteria reside within phagosomes of varying acidity based on the macrophage activation state. The ESX-1 secretion system [early secreted antigen 6 kilodaltons (ESAT-6) system-1] delivers protein virulence factors essential for phagosome lysis, facilitating infection. The mechanisms underlying ESX-1 lytic activity in heterogeneous environments remain unknown. Here we show that the canonical Type VII secretion system, ESX-1, orchestrates substrate switching in response to different environments. Growing\n                  <jats:italic>Mycobacterium marinum<\/jats:italic>\n                  at acidic pH resulted in substrate switching\n                  <jats:italic>in vitro<\/jats:italic>\n                  . Substrate switching was accompanied by significant changes to the levels of ESX-1 substrate transcripts, and to the levels of both ESX-1 substrates and chaperones at the protein level. We showed that specific ESX-1 transcripts were significantly upregulated\n                  <jats:italic>in vivo<\/jats:italic>\n                  , and that distinct substrate sets are required in an acidic infection model.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Pathogenic mycobacteria cause chronic and acute disease. Mycobacterial pathogens promote infection by transporting bacterial proteins into the host using ESX\/Type VII secretion systems. The ESX-1 system secretes proteins into the phagosome that release the bacteria into the cytoplasm and promote bacterial survival in the macrophage. We show that\n                    <jats:italic>Mycobacterium marinum,<\/jats:italic>\n                    an animal pathogen and model for studying ESX-1 and tuberculosis, switches which ESX-1 proteins are secreted in response to acidic pH, an infection relevant signal. We demonstrate that protein secretion reflects changes in substrate transcripts and in substrate and chaperone protein levels. Finally, we leveraged two infection models to support that ESX-1 substrate switching likely occurs during infection. Our findings support a model in which mycobacterial pathogens use different proteins to lyse macrophage phagosomes of different pH.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.04.703728","type":"posted-content","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T05:45:16Z","timestamp":1770270316000},"source":"Crossref","is-referenced-by-count":2,"title":["pH-responsive substrate switching in mycobacterial Type VII ESX secretion"],"prefix":"10.64898","author":[{"given":"Owen A.","family":"Collars","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame; Notre Dame, 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L.","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame; Notre Dame, 46556, USA"},{"name":"Department of Chemistry and Biochemistry, University of Notre Dame; Notre Dame, 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4354-0309","authenticated-orcid":false,"given":"Simon D.","family":"Weaver","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame; Notre Dame, 46556, USA"},{"name":"Department of Chemistry and Biochemistry, University of Notre Dame; Notre Dame, 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca J.","family":"Prest","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame; Notre Dame, 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb","family":"Manu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame; Notre Dame, 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopinath","family":"Viswanathan","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics & Microbiology, Integrative Immunobiology, and Cell Biology, Duke University School of Medicine; Durham, 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel M.","family":"Cronin","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame; Notre Dame, 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley S.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame; Notre Dame, 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3465-5518","authenticated-orcid":false,"given":"David M.","family":"Tobin","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics & Microbiology, Integrative Immunobiology, and Cell Biology, Duke University School of Medicine; Durham, 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew M.","family":"Champion","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Notre Dame; Notre Dame, 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6733-596X","authenticated-orcid":false,"given":"Patricia A.","family":"Champion","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame; Notre Dame, 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020905101474000_2026.02.04.703728v1.1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.96.2.137"},{"key":"2026020905101474000_2026.02.04.703728v1.2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.134.3.713"},{"key":"2026020905101474000_2026.02.04.703728v1.3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.142.1.1"},{"key":"2026020905101474000_2026.02.04.703728v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2007.09.006"},{"key":"2026020905101474000_2026.02.04.703728v1.5","doi-asserted-by":"crossref","unstructured":"Gouzy A , Healy C , Black KA , Rhee KY , Ehrt S . 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