{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T06:34:02Z","timestamp":1762842842536,"version":"build-2065373602"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Interleukin-6 (IL-6) plays a crucial role in inflammation and immune defense; however, its intracellular trafficking and the mechanisms regulating its expression remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated epithelial cell responses to poly(dA:dT) stimulation and group A\n                      <jats:italic>Streptococcus<\/jats:italic>\n                      infection, using depletion and overexpression assays, NF-\u03baB readouts, proteomics, co-immunoprecipitation, immunofluorescence imaging, and analysis of necrotizing soft tissue infection transcriptomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TBC1D9, a Rab GTPase-activating protein, selectively regulates IL-6: its depletion reduced IL-6 mRNA and protein levels without broadly affecting other pro-inflammatory cytokines. TBC1D9 maintained basal p65 phosphorylation but was dispensable for stimulus-induced NF-\u03baB activation, supporting the idea that homeostatic NF-\u03baB signaling is necessary for constitutive IL-6 transcription. Proteomics identified Rab29 as a TBC1D9 partner; co-immunoprecipitation showed preferential interaction with GTP-dependent Rab29, and the two proteins co-localized following stimulation and infection. Rab29 overexpression inhibited NF-\u03baB activation and IL-6 production, while Rab29 deficiency increased both, opposing TBC1D9\u2019s effect. Necrotizing soft tissue infection patients\u2019 datasets showed upregulation of TBC1D9 and IL-6-related pathways, revealing their clinical relevance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The TBC1D9\u2013Rab29 axis connects GTPase signaling and membrane trafficking to specifically regulate IL-6 in epithelial cells, revealing a non-traditional mechanism for modulating inflammation and a potential target in IL-6-driven diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2025.1688013","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T06:31:07Z","timestamp":1762842667000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A TBC1D9-Rab29 axis controls homeostatic NF-\u03baB signaling and selective IL-6 production in epithelial cells"],"prefix":"10.3389","volume":"15","author":[{"given":"Xin","family":"Hu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Nozawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuko","family":"Minowa-Nozawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazunori","family":"Murase","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ichiro","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"107492","DOI":"10.1016\/j.celrep.2020.03.056","article-title":"TBK1 and IKK\u03f5 Act redundantly to mediate STING-induced NF-\u03baB responses in myeloid cells","volume":"31","author":"Balka","year":"2020","journal-title":"Cell Rep."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00071","article-title":"Regulation of the NF-\u03baB-mediated transcription of inflammatory genes","volume":"5","author":"Bhatt","year":"2014","journal-title":"Front. 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