{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T15:11:12Z","timestamp":1793373072602,"version":"4.5.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"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. Immunol."],"abstract":"<jats:p>The innate immune and host-protective responses to viruses, such as the airway pathogen human metapneumovirus (HMPV), depend on interferons (IFNs) that is induced through TANK-binding kinase 1 (TBK1) and IFN regulatory factors (IRFs). The transcription factor IRF1 is important for host resistance against several viruses and has a key role in induction of IFN-\u03bb at mucosal surfaces. In most cell types IRF1 is expressed at very low levels, but its mRNA is rapidly induced when the demand for IRF1 activity arises. Despite general recognition of the importance of IRF1 to antiviral responses, the molecular mechanisms by which IRF1 is regulated during viral infections are not well understood. Here we identify the serine\/threonine kinase TBK1 and IFN-\u03b2 as critical regulators of IRF1 mRNA and protein levels in human monocyte-derived macrophages. We find that inhibition of TBK1 activity either by the semi-selective TBK1\/IKK\u03b5 inhibitor BX795 or by siRNA-mediated knockdown abrogates HMPV-induced expression of IRF1. Moreover, we show that canonical NF-\u03baB signaling is involved in IRF1 induction and that the TBK1\/IKK\u03b5 inhibitor BX795, but not siTBK1 treatment, impairs HMPV-induced phosphorylation of the NF-\u03baB subunit p65. At later time-points of the infection, IRF1 expression depended heavily on IFN-\u03b2-mediated signaling <jats:italic>via<\/jats:italic> the IFNAR-STAT1 pathway. Hence, our results suggest that TBK1 activation and TBK1\/IKK\u03b5-mediated phosphorylation of the NF-\u03baB subunit p65 control transcription of IRF1. Our study identifies a novel mechanism for IRF1 induction in response to viral infection of human macrophages that could be relevant not only to defense against HMPV, but also to other viral, bacterial and fungal pathogens.<\/jats:p>","DOI":"10.3389\/fimmu.2021.563336","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T05:35:50Z","timestamp":1624512950000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Human Metapneumovirus Induces IRF1 via TANK-Binding Kinase 1 and Type I IFN"],"prefix":"10.3389","volume":"12","author":[{"given":"Simon","family":"Loevenich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alix S.","family":"Spahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Rian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Boyartchuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marit Walbye","family":"Anthonsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1900","article-title":"Irfs: Master Regulators of Signalling by Toll-Like Receptors and Cytosolic Pattern-Recognition Receptors","volume":"6","author":"Honda","year":"2006","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01528-16","article-title":"HIV-1 Tat Recruits HDM2 E3 Ligase to Target IRF-1 for Ubiquitination and Proteasomal Degradation","volume":"7","author":"Remoli","year":"2016","journal-title":"MBio"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01151-18","article-title":"Distinctive Roles for Type I and Type II Interferons and Interferon Regulatory Factors in the Host Cell Defense Against Varicella-Zoster Virus","volume":"92","author":"Sen","year":"2018","journal-title":"J Virol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2017.120","article-title":"Respiratory Syncytial Virus Activates Epidermal Growth Factor Receptor to Suppress Interferon Regulatory Factor 1-Dependent Interferon-Lambda and Antiviral Defense in Airway Epithelium","volume":"11","author":"Kalinowski","year":"2018","journal-title":"Mucosal Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e1002230","DOI":"10.1371\/journal.ppat.1002230","article-title":"Interferon Regulatory Factor-1 (IRF-1) Shapes Both Innate and CD8(+) T Cell Immune Responses Against West Nile Virus Infection","volume":"7","author":"Brien","year":"2011","journal-title":"PloS Pathog"},{"key":"B6","doi-asserted-by":"publisher","first-page":"M9","DOI":"10.1016\/S0304-419X(97)00014-0","article-title":"IRF-1: The Transcription Factor Linking the Interferon Response and Oncogenesis","volume":"1333","author":"Taniguchi","year":"1997","journal-title":"Biochim Biophys Acta"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01019","article-title":"IRF1 Maintains Optimal Constitutive Expression of Antiviral Genes and Regulates the Early Antiviral Response","volume":"10","author":"Panda","year":"2019","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2915","article-title":"Diverse Intracellular Pathogens Activate Type III Interferon Expression From Peroxisomes","volume":"15","author":"Odendall","year":"2014","journal-title":"Nat Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.80.9.4501-4509.2006","article-title":"Lambda Interferon (IFN-Lambda), a Type III IFN, Is Induced by Viruses and IFNs and Displays Potent Antiviral Activity Against Select Virus Infections In Vivo","volume":"80","author":"Ank","year":"2006","journal-title":"J Virol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00272-10","article-title":"Lambda Interferon Renders Epithelial Cells of the Respiratory and Gastrointestinal Tracts Resistant to Viral Infections","volume":"84","author":"Mordstein","year":"2010","journal-title":"J Virol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.025","article-title":"Shared and Distinct Functions of Type I and Type III Interferons","volume":"50","author":"Lazear","year":"2019","journal-title":"Immunity"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.19.1.623","article-title":"IRF Family of Transcription Factors as Regulators of Host Defense","volume":"19","author":"Taniguchi","year":"2001","journal-title":"Annu Rev Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.2000.01163.x","article-title":"Degradation of Transcription Factor IRF-1 by the Ubiquitin-Proteasome Pathway. 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