{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:19:18Z","timestamp":1790223558455,"version":"4.1.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T00:00:00Z","timestamp":1464739200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T00:00:00Z","timestamp":1464739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKK\u025b (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)\/AKT-dependent manner. <jats:italic>Sike<\/jats:italic>-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (<jats:italic>Sike<\/jats:italic>-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1\/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure.<\/jats:p>","DOI":"10.1038\/ncomms11432","type":"journal-article","created":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T23:49:13Z","timestamp":1464824953000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Suppressor of IKK\u025b is an essential negative regulator of pathological cardiac hypertrophy"],"prefix":"10.1038","volume":"7","author":[{"given":"Ke-Qiong","family":"Deng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aibing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Xiao","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Yong","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingchen","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinglin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Hai","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongliang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,6,1]]},"reference":[{"key":"BFncomms11432_CR1","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/nrm1983","volume":"7","author":"J Heineke","year":"2006","unstructured":"Heineke, J. & Molkentin, J. D. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 7, 589\u2013600 (2006).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"BFncomms11432_CR2","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/nrcardio.2010.165","volume":"8","author":"AL Bui","year":"2011","unstructured":"Bui, A. L., Horwich, T. B. & Fonarow, G. C. Epidemiology and risk profile of heart failure. Nat. Rev. Cardiol. 8, 30\u201341 (2011).","journal-title":"Nat. Rev. Cardiol."},{"key":"BFncomms11432_CR3","doi-asserted-by":"publisher","first-page":"2019","DOI":"10.1038\/ncomms3019","volume":"4","author":"A Planavila","year":"2013","unstructured":"Planavila, A. et al. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat. Commun. 4, 2019 (2013).","journal-title":"Nat. Commun."},{"key":"BFncomms11432_CR4","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1056\/NEJMoa020265","volume":"347","author":"D Levy","year":"2002","unstructured":"Levy, D. et al. Long-term trends in the incidence of and survival with heart failure. N. Engl. J. Med. 347, 1397\u20131402 (2002).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms11432_CR5","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.1038\/ncomms2090","volume":"3","author":"A Ucar","year":"2012","unstructured":"Ucar, A. et al. The miRNA-212\/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat. Commun. 3, 1078 (2012).","journal-title":"Nat. Commun."},{"key":"BFncomms11432_CR6","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.abb.2014.08.007","volume":"562","author":"J Wang","year":"2014","unstructured":"Wang, J. et al. Tumor suppressor gene ING3 induces cardiomyocyte hypertrophy via inhibition of AMPK and activation of p38 MAPK signaling. Arch. Biochem. Biophys. 562, 22\u201330 (2014).","journal-title":"Arch. Biochem. Biophys."},{"key":"BFncomms11432_CR7","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1161\/CIRCULATIONAHA.114.010686","volume":"131","author":"M Bisserier","year":"2015","unstructured":"Bisserier, M. et al. Carabin protects against cardiac hypertrophy by blocking calcineurin, Ras, and Ca2+\/calmodulin-dependent protein kinase II signaling. Circulation 131, 390\u2013400 discussion 400 (2015).","journal-title":"Circulation"},{"key":"BFncomms11432_CR8","doi-asserted-by":"publisher","first-page":"1984","DOI":"10.1016\/j.cellsig.2015.06.009","volume":"27","author":"S Cotecchia","year":"2015","unstructured":"Cotecchia, S., Del Vescovo, C. D., Colella, M., Caso, S. & Diviani, D. The alpha1-adrenergic receptors in cardiac hypertrophy: Signaling mechanisms and functional implications. Cell. Signal. 27, 1984\u20131993 (2015).","journal-title":"Cell. Signal."},{"key":"BFncomms11432_CR9","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1172\/JCI62839","volume":"123","author":"JH van Berlo","year":"2013","unstructured":"van Berlo, J. H., Maillet, M. & Molkentin, J. D. Signaling effectors underlying pathologic growth and remodeling of the heart. J. Clin. Invest. 123, 37\u201345 (2013).","journal-title":"J. Clin. Invest."},{"key":"BFncomms11432_CR10","doi-asserted-by":"publisher","first-page":"3303","DOI":"10.1038\/ncomms4303","volume":"5","author":"DS Jiang","year":"2014","unstructured":"Jiang, D. S. et al. IRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling. Nat. Commun. 5, 3303 (2014).","journal-title":"Nat. Commun."},{"key":"BFncomms11432_CR11","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1007\/s00109-015-1281-3","volume":"93","author":"I Muthuramu","year":"2015","unstructured":"Muthuramu, I. et al. Selective homocysteine-lowering gene transfer attenuates pressure overload-induced cardiomyopathy via reduced oxidative stress. J. Mol. Med. 93, 609\u2013618 (2015).","journal-title":"J. Mol. Med."},{"key":"BFncomms11432_CR12","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.virol.2014.12.009","volume":"476","author":"MC Bajgelman","year":"2015","unstructured":"Bajgelman, M. C. et al. Preservation of cardiac function in left ventricle cardiac hypertrophy using an AAV vector which provides VEGF-A expression in response to p53. Virology 476, 106\u2013114 (2015).","journal-title":"Virology"},{"key":"BFncomms11432_CR13","doi-asserted-by":"publisher","first-page":"4018","DOI":"10.1038\/sj.emboj.7600863","volume":"24","author":"J Huang","year":"2005","unstructured":"Huang, J. et al. SIKE is an IKK epsilon\/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways. EMBO J. 24, 4018\u20134028 (2005).","journal-title":"EMBO J."},{"key":"BFncomms11432_CR14","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1152\/physrev.00054.2009","volume":"90","author":"BA Rose","year":"2010","unstructured":"Rose, B. A., Force, T. & Wang, Y. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol. Rev. 90, 1507\u20131546 (2010).","journal-title":"Physiol. Rev."},{"key":"BFncomms11432_CR15","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1093\/cvr\/cvu024","volume":"102","author":"N Kramann","year":"2014","unstructured":"Kramann, N., Hasenfuss, G. & Seidler, T. B-RAF and its novel negative regulator reticulocalbin 1 (RCN1) modulates cardiomyocyte hypertrophy. Cardiovasc. Res. 102, 88\u201396 (2014).","journal-title":"Cardiovasc. Res."},{"key":"BFncomms11432_CR16","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1161\/CIRCRESAHA.113.300536","volume":"114","author":"VB Pillai","year":"2014","unstructured":"Pillai, V. B., Sundaresan, N. R. & Gupta, M. P. Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging. Circ. Res. 114, 368\u2013378 (2014).","journal-title":"Circ. Res."},{"key":"BFncomms11432_CR17","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1073\/pnas.231619298","volume":"99","author":"CL Antos","year":"2002","unstructured":"Antos, C. L. et al. Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc. Natl Acad. Sci. USA 99, 907\u2013912 (2002).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms11432_CR18","doi-asserted-by":"publisher","first-page":"18612","DOI":"10.1074\/jbc.M112.440859","volume":"288","author":"JD Marion","year":"2013","unstructured":"Marion, J. D. et al. Mechanism of endogenous regulation of the type I interferon response by suppressor of IkappaB kinase epsilon (SIKE), a novel substrate of TANK-binding kinase 1 (TBK1). J. Biol. Chem. 288, 18612\u201318623 (2013).","journal-title":"J. Biol. Chem."},{"key":"BFncomms11432_CR19","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1161\/HYPERTENSIONAHA.115.05469","volume":"66","author":"X Jiang","year":"2015","unstructured":"Jiang, X. et al. Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy. Hypertension 66, 356\u2013367 (2015).","journal-title":"Hypertension"},{"key":"BFncomms11432_CR20","doi-asserted-by":"publisher","first-page":"2493","DOI":"10.1038\/nprot.2014.171","volume":"9","author":"Y Shao","year":"2014","unstructured":"Shao, Y. et al. CRISPR\/Cas-mediated genome editing in the rat via direct injection of one-cell embryos. Nat. Protoc. 9, 2493\u20132512 (2014).","journal-title":"Nat. Protoc."},{"key":"BFncomms11432_CR21","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.cyto.2008.07.011","volume":"43","author":"A Komuro","year":"2008","unstructured":"Komuro, A., Bamming, D. & Horvath, C. M. Negative regulation of cytoplasmic RNA-mediated antiviral signaling. Cytokine 43, 350\u2013358 (2008).","journal-title":"Cytokine"},{"key":"BFncomms11432_CR22","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1189\/jlb.0309189","volume":"86","author":"W Piao","year":"2009","unstructured":"Piao, W. et al. Endotoxin tolerance dysregulates MyD88- and Toll\/IL-1R domain-containing adapter inducing IFN-beta-dependent pathways and increases expression of negative regulators of TLR signaling. J. Leukoc. Biol. 86, 863\u2013875 (2009).","journal-title":"J. Leukoc. Biol."},{"key":"BFncomms11432_CR23","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1159\/000317690","volume":"2","author":"M Ito","year":"2010","unstructured":"Ito, M. et al. Peripheral B cells may serve as a reservoir for persistent hepatitis C virus infection. J. Innate Immun. 2, 607\u2013617 (2010).","journal-title":"J. Innate Immun."},{"key":"BFncomms11432_CR24","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.febslet.2013.01.052","volume":"587","author":"W Zhao","year":"2013","unstructured":"Zhao, W. Negative regulation of TBK1-mediated antiviral immunity. FEBS Lett. 587, 542\u2013548 (2013).","journal-title":"FEBS Lett."},{"key":"BFncomms11432_CR25","doi-asserted-by":"publisher","first-page":"7945","DOI":"10.1073\/pnas.0900818106","volume":"106","author":"Y Li","year":"2009","unstructured":"Li, Y. et al. ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response. Proc. Natl Acad. Sci. USA 106, 7945\u20137950 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms11432_CR26","doi-asserted-by":"publisher","first-page":"32277","DOI":"10.1074\/jbc.M111.236448","volume":"286","author":"L Leotoing","year":"2011","unstructured":"Leotoing, L. et al. A20-binding inhibitor of nuclear factor-kappaB (NF-kappaB)-2 (ABIN-2) is an activator of inhibitor of NF-kappaB (IkappaB) kinase alpha (IKKalpha)-mediated NF-kappaB transcriptional activity. J. Biol. Chem. 286, 32277\u201332288 (2011).","journal-title":"J. Biol. Chem."},{"key":"BFncomms11432_CR27","doi-asserted-by":"publisher","first-page":"840","DOI":"10.4049\/jimmunol.1301601","volume":"193","author":"SS Kim","year":"2014","unstructured":"Kim, S. S. et al. DOK3 is required for IFN-beta production by enabling TRAF3\/TBK1 complex formation and IRF3 activation. J. Immunol. 193, 840\u2013848 (2014).","journal-title":"J. Immunol."},{"key":"BFncomms11432_CR28","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.molcel.2011.01.019","volume":"41","author":"YH Ou","year":"2011","unstructured":"Ou, Y. H. et al. TBK1 directly engages Akt\/PKB survival signaling to support oncogenic transformation. Mol. Cell 41, 458\u2013470 (2011).","journal-title":"Mol. Cell"},{"key":"BFncomms11432_CR29","doi-asserted-by":"publisher","first-page":"6074","DOI":"10.1038\/ncomms7074","volume":"6","author":"J Yu","year":"2015","unstructured":"Yu, J. et al. Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nat. Commun. 6, 6074 (2015).","journal-title":"Nat. Commun."},{"key":"BFncomms11432_CR30","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1093\/cvr\/cvu068","volume":"102","author":"MM Lopez-Olaneta","year":"2014","unstructured":"Lopez-Olaneta, M. M. et al. Induction of the calcineurin variant CnAbeta1 after myocardial infarction reduces post-infarction ventricular remodelling by promoting infarct vascularization. Cardiovasc. Res. 102, 396\u2013406 (2014).","journal-title":"Cardiovasc. Res."},{"key":"BFncomms11432_CR31","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1161\/HYPERTENSIONAHA.113.02083","volume":"63","author":"DS Jiang","year":"2014","unstructured":"Jiang, D. S. et al. Interferon regulatory factor 9 protects against cardiac hypertrophy by targeting myocardin. Hypertension 63, 119\u2013127 (2014).","journal-title":"Hypertension"},{"key":"BFncomms11432_CR32","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/nbt.1775","volume":"29","author":"F Zhang","year":"2011","unstructured":"Zhang, F. et al. Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription. Nature Biotechnol. 29, 149\u2013153 (2011).","journal-title":"Nature Biotechnol."},{"key":"BFncomms11432_CR33","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1161\/HYPERTENSIONAHA.113.02653","volume":"63","author":"DS Jiang","year":"2014","unstructured":"Jiang, D. S. et al. Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy. Hypertension 63, 713\u2013722 (2014).","journal-title":"Hypertension"},{"key":"BFncomms11432_CR34","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1161\/HYPERTENSIONAHA.111.00614","volume":"61","author":"DS Jiang","year":"2013","unstructured":"Jiang, D. S. et al. Role of interferon regulatory factor 4 in the regulation of pathological cardiac hypertrophy. Hypertension 61, 1193\u20131202 (2013).","journal-title":"Hypertension"},{"key":"BFncomms11432_CR35","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1161\/HYPERTENSIONAHA.114.03229","volume":"64","author":"DS Jiang","year":"2014","unstructured":"Jiang, D. S. et al. Interferon regulatory factor 1 is required for cardiac remodeling in response to pressure overload. Hypertension 64, 77\u201386 (2014).","journal-title":"Hypertension"},{"key":"BFncomms11432_CR36","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1161\/HYPERTENSIONAHA.115.05183","volume":"66","author":"X Zhu","year":"2015","unstructured":"Zhu, X. et al. Exacerbating pressure overload-induced cardiac hypertrophy: novel role of adaptor molecule Src homology 2-B3. Hypertension 66, 571\u2013581 (2015).","journal-title":"Hypertension"},{"key":"BFncomms11432_CR37","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1161\/01.RES.0000215985.18538.c4","volume":"98","author":"T Oka","year":"2006","unstructured":"Oka, T. et al. Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability. Circ. Res. 98, 837\u2013845 (2006).","journal-title":"Circ. Res."},{"key":"BFncomms11432_CR38","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1007\/s00109-012-0883-2","volume":"90","author":"ZY Bian","year":"2012","unstructured":"Bian, Z. Y. et al. Disruption of mindin exacerbates cardiac hypertrophy and fibrosis. J. Mol. Med. 90, 895\u2013910 (2012).","journal-title":"J. Mol. Med."}],"updated-by":[{"DOI":"10.1038\/s41467-023-38331-w","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T00:00:00Z","timestamp":1684972800000}}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms11432.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms11432","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms11432.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T10:02:09Z","timestamp":1686218529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms11432"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,1]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,9,1]]}},"alternative-id":["BFncomms11432"],"URL":"https:\/\/doi.org\/10.1038\/ncomms11432","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,1]]},"assertion":[{"value":"18 October 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 March 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11432"}}