{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:23:59Z","timestamp":1787203439118,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,4]]},"group-title":"Systems Biology","reference-count":105,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Intramural Research Program, NIH","award":["AI001085-17"],"award-info":[{"award-number":["AI001085-17"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Sensing of tissue injury or infection by Toll-like receptors (TLRs) must rapidly mobilize host defense, but that activation must also be terminated on an appropriate time scale to avoid sustained, tissue-damaging inflammation. The full network of molecular interactions that governs both the rapid onset and the properly timed shutoff of TLR signaling remains incompletely characterized at a deep mechanistic level. To this end, we built a rule-based model of mouse macrophage TLR4 signaling at the molecular-interaction level, parameterized with measured protein copy numbers, RNA-seq-based abundance estimates, literature- and structure-informed reaction rates, and 979 dynamic experimental constraints, achieving a level of granularity beyond that of prior TLR models. The trained model reproduced much of the TLR4-induced NF-\u03baB and MAP kinase response, but it consistently failed to capture deactivation of MyD88, TRAF6-associated species, and IKK\u03b1\/\u03b2. Rather than treating this as simple model error, we used the recurrent failure as a biological signal that localized missing regulation to the proximalMyD88-IRAK-TRAF6 module and motivated experimental evaluation of IKK\u03b5 and its scaffold TANK. Loss of IKK\u03b5 enhanced transcriptional, cytokine, MAP kinase, and NF-\u03baB responses to MyD88-specific TLR ligands, and TANK deficiency produced a similar cellular phenotype while abolishing stimulus-induced IKK\u03b5 phosphorylation. Deficiency of either protein increased IRAK1and TRAF6 ubiquitination without increasing MyD88 ubiquitination, placing the inhibitory checkpoint at or immediately downstream of the IRAK1-TRAF6 ubiquitin-signaling node. Overlapping but non-identical in vivo phenotypes further supported a shared regulatory axis with additional protein-specific functions. Together, these findings illustrate a model-experiment discovery cycle in which quantitative pathway discordance identifies missing biology, revealing a TANK-dependent IKK\u03b5 checkpoint that restrains MyD88-driven inflammation.<\/jats:p>","DOI":"10.64898\/2026.08.03.742528","type":"posted-content","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:30:40Z","timestamp":1785850240000},"source":"Crossref","is-referenced-by-count":0,"title":["Quantitative Modeling of TLR Signaling Reveals Missing Negative Feedback Guiding Identification of TANK-IKK\u03b5 Checkpoint"],"prefix":"10.64898","author":[{"given":"Nathan P.","family":"Manes","sequence":"first","affiliation":[{"name":"Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengkai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Computational Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Lin","sequence":"additional","affiliation":[{"name":"Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Sun","sequence":"additional","affiliation":[{"name":"Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio A.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony A.","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Shao","sequence":"additional","affiliation":[{"name":"Computational Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Calzola","sequence":"additional","affiliation":[{"name":"Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline R.","family":"Kaplan-Stafford","sequence":"additional","affiliation":[{"name":"Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A.","family":"Gottschalk","sequence":"additional","affiliation":[{"name":"Dept. of Immunology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Marino","sequence":"additional","affiliation":[{"name":"Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doeun","family":"Kim","sequence":"additional","affiliation":[{"name":"Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald N.","family":"Germain","sequence":"additional","affiliation":[{"name":"Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Meier-Schellersheim","sequence":"additional","affiliation":[{"name":"Computational Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain D. 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