{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:27:30Z","timestamp":1790400450517,"version":"4.1.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T00:00:00Z","timestamp":1575417600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T00:00:00Z","timestamp":1575417600000},"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":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Upon necroptosis activation, receptor interacting serine\/threonine kinase (RIPK)1 and RIPK3 form a necrosome complex with pseudokinase mixed lineage kinase-like (MLKL). Although protein phosphorylation is a key event for RIPK1 and RIPK3 activation in response to a necroptosis signal, relatively little is known about other factors that might regulate the activity of these kinases or necrosome formation. Through a gain-of-function screen with 546 kinases and 127 phosphatases, we identified casein kinase 1 gamma (CK1\u03b3) as a candidate necroptosis-promoting factor. Here, we show that the decreased activity or amounts of CK1\u03b31 and CK1\u03b33, either by treatment with a chemical inhibitor or knockdown in cells, reduced TNF\u03b1-induced necroptosis. Conversely, ectopic expression of CK1\u03b31 or CK1\u03b33 exacerbated necroptosis, but not apoptosis. Similar to RIPK1 and RIPK3, CK1\u03b31 was also cleaved at Asp<jats:sup>343<\/jats:sup> by caspase-8 during apoptosis. CK1\u03b31 and CK1\u03b33 formed a protein complex and were recruited to the necrosome harboring RIPK1, RIPK3 and MLKL. In particular, an autophosphorylated form of CK1\u03b33 at Ser<jats:sup>344\/345<\/jats:sup> was detected in the necrosome and was required to mediate the necroptosis. In addition, in vitro assays with purified proteins showed that CK1\u03b3 phosphorylated RIPK3, affecting its activity, and in vivo assays showed that the CK1\u03b3-specific inhibitor Gi prevented abrupt death in mice with hypothermia in a model of TNF\u03b1-induced systemic inflammatory response syndrome. Collectively, these data suggest that CK1\u03b31 and CK1\u03b33 are required for TNF\u03b1-induced necroptosis likely by regulating RIPK3.<\/jats:p>","DOI":"10.1038\/s41419-019-2146-4","type":"journal-article","created":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T19:03:28Z","timestamp":1575486208000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Casein kinase-1\u03b31 and 3 stimulate tumor necrosis factor-induced necroptosis through RIPK3"],"prefix":"10.1038","volume":"10","author":[{"given":"Song-Yi","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunjoo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathena Meiling","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaemin","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1350-2056","authenticated-orcid":false,"given":"Ayaz","family":"Najafov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhah","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7016-2417","authenticated-orcid":false,"given":"Soosung","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaomeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junying","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Keun","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,4]]},"reference":[{"key":"2146_CR1","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.ceb.2009.12.003","volume":"22","author":"DE Christofferson","year":"2010","unstructured":"Christofferson, D. E. & Yuan, J. Necroptosis as an alternative form of programmed cell death. Curr. Opin. Cell Biol. 22, 263\u2013268 (2010).","journal-title":"Curr. Opin. Cell Biol."},{"key":"2146_CR2","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/nature09852","volume":"471","author":"A Oberst","year":"2011","unstructured":"Oberst, A. et al. Catalytic activity of the caspase-8-FLIPL complex inhibits RIPK3-dependent necrosis. Nature 471, 363\u2013367 (2011).","journal-title":"Nature"},{"key":"2146_CR3","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/nature09857","volume":"471","author":"WJ Kaiser","year":"2011","unstructured":"Kaiser, W. J. et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471, 368\u2013372 (2011).","journal-title":"Nature"},{"key":"2146_CR4","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/nature09878","volume":"471","author":"H Zhang","year":"2011","unstructured":"Zhang, H. et al. Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 471, 373\u2013376 (2011).","journal-title":"Nature"},{"key":"2146_CR5","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1016\/j.cell.2009.05.021","volume":"137","author":"S He","year":"2009","unstructured":"He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-\u03b1. Cell 137, 1100\u20131111 (2009).","journal-title":"Cell"},{"key":"2146_CR6","doi-asserted-by":"publisher","first-page":"12024","DOI":"10.1073\/pnas.1305538110","volume":"110","author":"A Linkermann","year":"2013","unstructured":"Linkermann, A. et al. Two independent pathways of regulated necrosis mediate ischemia\u2013reperfusion injury. Proc. Natl Acad. Sci. USA 110, 12024\u201312029 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2146_CR7","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1016\/j.cell.2014.04.018","volume":"157","author":"CP Dillon","year":"2014","unstructured":"Dillon, C. P. et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 157, 1189\u20131202 (2014).","journal-title":"Cell"},{"key":"2146_CR8","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1101\/gad.312561.118","volume":"32","author":"B Shan","year":"2018","unstructured":"Shan, B., Pan, H., Najafov, A. & Yuan, J. Necroptosis in development and diseases. Genes Dev. 32, 327\u2013340 (2018).","journal-title":"Genes Dev."},{"key":"2146_CR9","doi-asserted-by":"publisher","first-page":"2514","DOI":"10.1101\/gad.13.19.2514","volume":"13","author":"Y Lin","year":"1999","unstructured":"Lin, Y., Devin, A., Rodriguez, Y. & Liu, Z. Cleavage of the death domain kinase RIP by Caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13, 2514\u20132526 (1999).","journal-title":"Genes Dev."},{"key":"2146_CR10","doi-asserted-by":"publisher","first-page":"2056","DOI":"10.1016\/j.cellsig.2007.05.016","volume":"19","author":"S Feng","year":"2007","unstructured":"Feng, S. et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal. 19, 2056\u20132067 (2007).","journal-title":"Cell Signal."},{"key":"2146_CR11","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1002\/embr.201337970","volume":"15","author":"M Murphy","year":"2014","unstructured":"Murphy, M. & Silke, J. Ars Moriendi; the art of dying well \u2013 new insights into the molecular pathways of necroptotic cell death. EMBO Rep. 15, 155\u2013164 (2014).","journal-title":"EMBO Rep."},{"key":"2146_CR12","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/nchembio.83","volume":"4","author":"A Degterev","year":"2008","unstructured":"Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 4, 313\u2013321 (2008).","journal-title":"Nat. Chem. Biol."},{"key":"2146_CR13","doi-asserted-by":"publisher","first-page":"16247","DOI":"10.1074\/jbc.M112.435545","volume":"288","author":"W Chen","year":"2013","unstructured":"Chen, W. et al. Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling. J. Biol. Chem. 288, 16247\u201316261 (2013).","journal-title":"J. Biol. Chem."},{"key":"2146_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00406-w","volume":"8","author":"J Geng","year":"2017","unstructured":"Geng, J. et al. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat. Commun. 8, 359 (2017).","journal-title":"Nat. Commun."},{"key":"2146_CR15","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1016\/j.celrep.2015.02.051","volume":"10","author":"Ofengeim","year":"2015","unstructured":"Ofengeim et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 10, 1836\u20131849 (2015).","journal-title":"Cell Rep."},{"key":"2146_CR16","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.cell.2011.11.031","volume":"148","author":"L Sun","year":"2012","unstructured":"Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213\u2013227 (2012).","journal-title":"Cell"},{"key":"2146_CR17","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1038\/ncb3608","volume":"19","author":"Y Dondelinger","year":"2017","unstructured":"Dondelinger, Y. et al. MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. Nat. Cell Biol. 19, 1237\u20131247 (2017).","journal-title":"Nat. Cell Biol."},{"key":"2146_CR18","doi-asserted-by":"crossref","unstructured":"Jaco, I. et al. MK2 phosphorylates RIPK1 to prevent TNF-induced cell death. Mol. Cell 66, 698\u2013710, e695. (2017).","DOI":"10.1016\/j.molcel.2017.05.003"},{"key":"2146_CR19","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1038\/s41556-018-0229-6","volume":"12","author":"E Lafont","year":"2018","unstructured":"Lafont, E. et al. TBK1 and IKK\u03b5 prevent TNF-induced cell death by RIPK1 phosphorylation. Nat. Cell Biol. 12, 1389\u20131399 (2018).","journal-title":"Nat. Cell Biol."},{"key":"2146_CR20","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1016\/j.cell.2018.07.041","volume":"6","author":"D Xu","year":"2018","unstructured":"Xu, D. et al. TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging. Cell. 6, 1477\u20131491 (2018).","journal-title":"Cell."},{"key":"2146_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.molcel.2015.07.032","volume":"60","author":"Y Dondelinger","year":"2015","unstructured":"Dondelinger, Y. et al. NF-kB-independent role of IKKa\/IKKb in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol. Cell 60, 1\u201314 (2015).","journal-title":"Mol. Cell"},{"key":"2146_CR22","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/ncb3120","volume":"17","author":"W Chen","year":"2015","unstructured":"Chen, W. et al. Ppm1b negatively regulates necroptosis through dephosphorylating Rip3. Nat. Cell Biol. 17, 434\u2013444 (2015).","journal-title":"Nat. Cell Biol."},{"key":"2146_CR23","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-13-231","volume":"13","author":"B Schittek","year":"2014","unstructured":"Schittek, B. & Sinnberg, T. Biological functions of casein kinase 1 isoforms and putative roles in tumorigenesis. Mol. Cancer 13, 231 (2014).","journal-title":"Mol. Cancer"},{"key":"2146_CR24","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/j.biocel.2010.12.004","volume":"43","author":"J Cheong","year":"2011","unstructured":"Cheong, J. & Virshup, D. Casein kinase 1: complexity in the family. Int. J. Biochem. Cell Biol. 43, 465\u2013469 (2011).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2146_CR25","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/sj.embor.7400048","volume":"5","author":"G Rena","year":"2004","unstructured":"Rena, G., Bain, J., Elliott, M. & Cohen, P. D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO Rep. 5, 60\u201365 (2004).","journal-title":"EMBO Rep."},{"key":"2146_CR26","doi-asserted-by":"publisher","first-page":"5392","DOI":"10.1016\/j.bmcl.2012.07.046","volume":"22","author":"Z Hua","year":"2012","unstructured":"Hua, Z. et al. 2-Phenylamino-6-cyano-1H-benzimidazole-based isoform selective casein kinase 1 gamma (CK1\u03b3) inhibitors. Bioorg. Med. Che. Lett. 22, 5392\u20135395 (2012).","journal-title":"Bioorg. Med. Che. Lett."},{"key":"2146_CR27","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/nchembio711","volume":"1","author":"A Degterev","year":"2005","unstructured":"Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112\u2013119 (2005).","journal-title":"Nat. Chem. Biol."},{"key":"2146_CR28","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.cell.2012.06.019","volume":"150","author":"J Li","year":"2012","unstructured":"Li, J. et al. The RIP1\/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150, 339\u2013350 (2012).","journal-title":"Cell"},{"key":"2146_CR29","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.cell.2011.11.030","volume":"148","author":"Z Wang","year":"2012","unstructured":"Wang, Z., Jiang, H., Chen, S., Du, F. & Wang, X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 148, 228\u2013243 (2012).","journal-title":"Cell"},{"key":"2146_CR30","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.molcel.2014.03.003","volume":"54","author":"H Wang","year":"2014","unstructured":"Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133\u2013146 (2014).","journal-title":"Mol. Cell"},{"key":"2146_CR31","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1016\/j.immuni.2011.09.020","volume":"35","author":"L Duprez","year":"2010","unstructured":"Duprez, L. et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35, 908\u2013918 (2010).","journal-title":"Immunity"},{"key":"2146_CR32","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1126\/science.1249361","volume":"343","author":"K Newton","year":"2014","unstructured":"Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357\u20131360 (2014).","journal-title":"Science"},{"key":"2146_CR33","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1038\/cdd.2012.133","volume":"20","author":"A Degterev","year":"2013","unstructured":"Degterev, A., Maki, J. L. & Yuan, J. Activity and specificity of necrostatin-1, small-molecule inhibitor of RIP1 kinase. Cell Death. Differ. 20, 366 (2013).","journal-title":"Cell Death. Differ."},{"key":"2146_CR34","doi-asserted-by":"crossref","unstructured":"Najafov, A. et al. TAM kinases promote necroptosis by regulating oligomerization of MLKL. Mol. Cell 75, 457\u2013468, e4 (2019).","DOI":"10.1016\/j.molcel.2019.05.022"},{"key":"2146_CR35","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1042\/BJ20101732","volume":"433","author":"A Najafov","year":"2011","unstructured":"Najafov, A. et al. Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1. Biochem. J. 433, 357\u2013369 (2011).","journal-title":"Biochem. J."},{"key":"2146_CR36","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1038\/nature04170","volume":"438","author":"G Davidson","year":"2005","unstructured":"Davidson, G. et al. Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438, 867\u2013872 (2005).","journal-title":"Nature"},{"key":"2146_CR37","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/s41556-017-0022-y","volume":"20","author":"Z Yang","year":"2018","unstructured":"Yang, Z. et al. RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis. Nat. Cell Biol. 20, 186\u2013197 (2018).","journal-title":"Nat. Cell Biol."},{"key":"2146_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14329","volume":"8","author":"Y Zhang","year":"2017","unstructured":"Zhang, Y. et al. RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat. Commun. 8, 14329 (2017).","journal-title":"Nat. Commun."},{"key":"2146_CR39","doi-asserted-by":"publisher","first-page":"12717","DOI":"10.1074\/jbc.270.21.12717","volume":"270","author":"L Zhai","year":"1995","unstructured":"Zhai, L. et al. Casein kinase I\u03b3 subfamily. J. Biol. Chem. 270, 12717\u201312724 (1995).","journal-title":"J. Biol. Chem."},{"key":"2146_CR40","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/ncb2883","volume":"16","author":"Z Cai","year":"2013","unstructured":"Cai, Z. et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16, 55\u201365 (2013).","journal-title":"Nat. Cell Biol."}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-019-2146-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-019-2146-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-019-2146-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T18:03:40Z","timestamp":1671213820000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-019-2146-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,4]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["2146"],"URL":"https:\/\/doi.org\/10.1038\/s41419-019-2146-4","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,4]]},"assertion":[{"value":"17 September 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 September 2019","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2019","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 December 2019","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"923"}}