{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:27:30Z","timestamp":1792787250811,"version":"4.5.0"},"reference-count":21,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P35951"],"award-info":[{"award-number":["P35951"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Federal Ministry of Research Technology and Space","award":["01KI2120A"],"award-info":[{"award-number":["01KI2120A"]}],"id":[{"id":"https:\/\/ror.org\/04pz7b180","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The opportunistic mold\n                      <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                      , a WHO-priority fungal pathogen, causes life-threatening invasive infections in immunocompromised patients. A major antifungal drug target is the ergosterol biosynthesis pathway, primarily regulated by the transcription factors SrbA and AtrR. Recently, we identified RttA as an additional regulator of sterol homeostasis that mediates the activation of the sterol C24-methyltransferase-encoding gene\n                      <jats:italic toggle=\"yes\">erg6<\/jats:italic>\n                      . Here, we demonstrate that overexpression of\n                      <jats:italic toggle=\"yes\">rttA<\/jats:italic>\n                      leads to elevated production of the secondary metabolite fumicycline via induction of\n                      <jats:italic toggle=\"yes\">fccR<\/jats:italic>\n                      , coding for the principal transcriptional activator of fumicycline biosynthesis. Lack of\n                      <jats:italic toggle=\"yes\">fccR<\/jats:italic>\n                      blocked activation of fumicycline biosynthetic genes (\n                      <jats:italic toggle=\"yes\">fccA-fccE<\/jats:italic>\n                      ) during\n                      <jats:italic toggle=\"yes\">rttA<\/jats:italic>\n                      overexpression, highlighting the indispensable role of FccR for activation of this cluster. In contrast,\n                      <jats:italic toggle=\"yes\">rttA<\/jats:italic>\n                      inactivation did not abolish fumicycline production during\n                      <jats:italic toggle=\"yes\">fccR<\/jats:italic>\n                      overexpression or during co-cultivation with\n                      <jats:italic toggle=\"yes\">Streptomyces rapamycinicus<\/jats:italic>\n                      . In addition to\n                      <jats:italic toggle=\"yes\">fccA-fccE<\/jats:italic>\n                      , our findings reveal a crucial role of FccR for the upregulation of a gene located adjacent to the fumicycline biosynthesis cluster, here termed\n                      <jats:italic toggle=\"yes\">fccF<\/jats:italic>\n                      . Deletion of\n                      <jats:italic toggle=\"yes\">fccF<\/jats:italic>\n                      severely diminished the conversion of fumicycline B into fumicycline C, uncovering FccF as fumicycline B O-acetyltransferase. Intriguingly, during\n                      <jats:italic toggle=\"yes\">fccR<\/jats:italic>\n                      overexpression and resulting fumicycline overproduction, inactivation of\n                      <jats:italic toggle=\"yes\">fccF<\/jats:italic>\n                      caused growth defects, likely due to precursor toxicity. Together, these findings broaden our understanding of fungal secondary metabolite regulation and reveal a novel role of RttA in the activation of\n                      <jats:italic toggle=\"yes\">fccR<\/jats:italic>\n                      encoding the cluster-specific regulator that activates fumicycline production, including FccF, the terminal acetyltransferase in the pathway.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                        is a major opportunistic fungal pathogen that causes severe infections in immunocompromised individuals and represents a significant global health threat. Understanding the regulatory networks controlling fungal metabolism is important for identifying potential therapeutic vulnerabilities. Here, we uncover a previously unrecognized role for the sterol homeostasis regulator RttA in activating fumicycline production through induction of the pathway-specific transcription factor FccR. We further show that FccR controls expression of an additional biosynthetic gene,\n                        <jats:italic toggle=\"yes\">fccF<\/jats:italic>\n                        , and identify FccF as the terminal O-acetyltransferase required for conversion of fumicycline B to fumicycline C. Disruption of this final biosynthetic step impairs fungal growth during metabolite overproduction, indicating that accumulation of fumicycline B or related intermediates can negatively affect fungal growth. Together, these findings expand our understanding of fungal secondary metabolite regulation and provide new insights into the organization and function of the fumicycline biosynthetic pathway.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02288-26","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:41:26Z","timestamp":1788529286000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Overexpression of\n                    <i>rttA<\/i>\n                    leads to activation of the fumicycline biosynthesis cluster including the O-acetyltransferase encoding\n                    <i>fccF<\/i>"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3544-3358","authenticated-orcid":false,"given":"Lukas","family":"Bir\u0161tonas","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/054pv6659","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Molecular Biology, Biocenter, Medical University of Innsbruck","place":["Innsbruck, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Tr\u00f6ger-G\u00f6rler","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/055s37c97","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)","place":["Jena, Germany"]},{"id":[{"id":"https:\/\/ror.org\/05qpz1x62","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Microbiology, Friedrich Schiller University (FSU)","place":["Jena, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3316-7769","authenticated-orcid":true,"given":"Ingo","family":"Bauer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/054pv6659","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Molecular Biology, Biocenter, Medical University of Innsbruck","place":["Innsbruck, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birte","family":"Mertens","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/054pv6659","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Molecular Biology, Biocenter, Medical University of Innsbruck","place":["Innsbruck, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrick","family":"Schweder","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/055s37c97","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular 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