[email protected]) ([email protected]; correspondence for *Authors Place, Thomas Danny USA. 262 38105, Hospital, TN Research Memphis, Children’s Jude St. Immunology, fGagw wthakRa,GagwG11D UK. 1BD, G61 Glasgow Road, Switchback Glasgow, of i nte a o-ppoi ehnsso eldeath cell Tait of G. W. mechanisms Stephen non-apoptotic – way another Die COMMENTARY ß hrpui otx o xml,t nbetekligof a killing in the enable death to cell 1 example, manipulate for – to context opportunities might therapeutic death new apoptosis. cell of non-apoptotic independently engage provide than to occur ability or other the serve apoptosis Importantly, can programmes failed death up cell death back non-apoptotic to here, cell discuss we upon interest As Increasing apoptosis. centred 2008). al., recently et Taylor al., has 2013; that et al., McIlwain et death 2011; Parrish hallmarks, (Green, cell 2013; extensively biochemical reviewed rapid of been and about has activation and bring morphological the to distinctive of the order requires displays molecular form in is Apoptosis proteases conserved apoptosis specific death. caspase evolutionary Unquestionably, cell utilise most cell. programmed the and and kill best-characterised that death suicide to cell In of demise. machinery or cellular forms own – active its upon to damage constitute into focus contributes overwhelming we divided itself of Commentary, cell be this result the can that a dies such as cell active, a occurring which – by injury. passive pathologies, means and diverse the neurodegeneration underpins Generally, death autoimmunity, cell cancer, immunity. little of including too to variety or embryogenesis a much in from roles Too ranging key plays processes death biological cell regulated animals, all In Introduction Pyroptosis Necroptosis, Mitochondria, RIPK3, MLKL, WORDS: KEY and about roles know pyroptosis potential we what death, mechanism, death outline their We cell cell death. of cell autophagic forms caspase-independent necroptosis, non-apoptotic Commentary, regulated including this death or several In apoptosis execute. discuss cell to of we fail independently apoptosis non-apoptotic should triggered engaged either as are These such be exist, can pyroptosis. also requires modalities death and that cell of appreciated process necroptosis forms been non-apoptotic has a it various Recently apoptosis, that proteases. caspase is of of death activation form best-studied cell The cells. programmed including damaged of processes, destruction immune and the many multicellular of system in development all embryogenesis, essential during for sculpting is tissue crucial death is Cell death organisms. cell programmed Regulated, ABSTRACT set fcl death. inflammatory cell on discussion of which our aspects by focusing matters, means actually the dies that cell arguing a data review we Finally, questions. acrRsac KBasnIsiue nttt fCne cecs University Sciences, Cancer of Institute Institute, Beatson UK Research Cancer 04 ulse yTeCmayo ilgssLd|Junlo elSine(04 2,23–14doi:10.1242/jcs.093575 2135–2144 127, (2014) Science Cell of Journal | Ltd Biologists of Company The by Published 2014. 1, ,GbilIchim Gabriel *, nvivo in n eieoutstanding define and 1 n oga .Green R. Douglas and 2 eatetof Department o h oeo eldahipcso muiyand immunity on impacts death cell of on ask mode focus we we inflammation. Specifically, the dies. this, cell Following a how how questions. matter really outstanding it roles whether outline and occurrence they we their how and and death, another cell one with programmed discuss intersect non-apoptotic we of Commentary, forms this major In cells. cancer apoptosis-resistant ppoi,udrcniin fcsaeihbto,cntrigger trigger can that inhibition, stimuli caspase several of Green below, conditions 2011; discussed al., under As et apoptosis, (Galluzzi 2011). death al., cell et a of is morphologically type it active Although that regulated in 2005). substantially differs necroptosis al., necrosis, resembling et (Degterev called death necroptosis cell of form non-apoptotic a engage can stimuli Various Necroptosis hn 03.RP1adRP3itrc hog receptor- of activation through the (RHIM) to sequentially interact motifs leads This interaction proteins. RIPK3 both in homotypic present and (RIP) protein RIPK1 interacting and (Moriwaki 2013). RIPK3 and RIPK1 Chan, between interaction TRADD, an protein to adaptor data leads the of current recruitment the necroptosis, through binding receptor–ligand indirectly, of TNF whereby initiation model simplified TNF-dependent the a supports During both 2013). mediating Yuan, in also role RIPK1 factor necroptosis, nuclear well-established Besides 2010). a al., et has (Moujalled Upton settings 2013; some al., 2000; in et al., dispensable et necroptosis, appears Holler TNF-induced RIPK1 for 2009; essential whereas al., is et RIPK3 2009). 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(Miura, often activation outgrowth has forebrain This display sometimes MOMP intervention. therapeutic cancer; cells of impart site to possible malignant al., a found promote provides et to been therefore (Schmitt has resistance can CICD CICD caspase chemotherapeutic of subvert inhibition MOMP also disabling Moreover, can 2002). cells of settings, these some presumably downstream promote to in expected activation be Indeed, might CICD tumorigenesis. and Consequently, apoptosis function. of caspase disabled inhibition have mechanism that suppressor cells vertebrates, tumour killing development higher effective by an In form embryonic 1998). also al., might et during mitochondrial- CICD Yoshida 1998; for least al., et substitute at (Cecconi can apoptosis, CICD postnatal (E)7 to dependent that leads day Apaf1 embryonic arguing of deletion at contrast, lethality, In lethality 2001). embryonic al., et deletion early (Wei combined their to and leads MOMP for often required to are death Bak unable cell and Bax of might therefore mode CICD of that significant 10% are implying a CICD, up be (and undergo that mice suggests wild-type Apaf1 in apoptosis) cells lack trigger wild- and that caspases between activate mice death cell and interdigital type of analysis morphological nsm icmtne,clscnudroMM n even and MOMP undergo can cells circumstances, some In ieta r eiin natvtn apssdwsra of downstream caspases activating in deficient are that Mice curneadrlso CICD of roles and occurrence nvivo in nvivo in slcig Comparative lacking. is Catne l,1999). al., et (Chautan nvitro in and fet fkyfcosivle ntepoes Further process. the in involved factors key non-cytotoxic of additional by cell hampered effects non-apoptotic is detect necroptosis dependent to approaches death definitive develop to aiiaercgiinadeglmn fteaottccl by cell apoptotic cells to apoptotic the signals Consequently, ‘eat-me’ of 2011). and (Ravichandran, engulfment phagocytes cells and phagocytic recognition attract ‘find- facilitate to generate signals also processes me’ an caspase-dependent In release. cell, vesicles anti- DAMP apoptotic plasma-membrane-bound minimising various the thereby into bodies, of even al., apoptotic packaged components called et by apoptosis, are (Green undergoes or cell case cell release dying the a always as non- DAMP not Firstly, 2009). is considered this minimises although mechanisms, release. and generally DAMP regulating inflammatory, is of means effects, major Apoptosis of deleterious represent type if and have death extent but cell the also pathogen, both Importantly, can 2008). alert cell-death-inducing autoimmunity. including it help a Rock, inappropriately might to and triggered recognition system (Kono immune and TLR the release mechanisms through DAMP cells other Importantly, dendritic and activate to and signalling serve they macrophages alarmins, neighbouring or (DAMPs) damage-associated as patterns to molecular referred Collectively cells. inflammation. from upon released impacts death many cell upon for discussion of our question type focus this will the we how to brevity, of ‘yes’ reasons resounding For reasons. a answer dies? 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Journal of Cell Science hn . hu . i . hn,C . hn,X,W,X,Zag . a H., Ma, Y., Zhang, X., Wu, X., Zheng, Q., C. P. Zhong, Golstein, L., Li, and Z., Zhou, P. W., Gruss, Chen, F., Cecconi, G., Chazal, M., Chautan, and A. Hoffmann, J., Yuan, C., Lynch, A., Degterev, R., D. Beisner, L., I. Ch’en, P. Gruss, and A. K. Roth, I., Wu, B. Y., Meyer, Ward, G., J., Alvarez-Bolado, F., Liu, Cecconi, S., Choksi, C., H. Chiang, J., Zhao, S., Jitkaew, Z., Cai, Y., H. Chen, J., Chen, J., Fan, J., J. Kamphorst, A., Lau, A., R., M. Mathew, K., Ermolaeva, Bray, G., Loo, van S., P. Welz, D., Preukschat, C., M. Bonnet, D. J. Lane, and M. V. Betin, aiuaei nvrospoessicuigcne and cancer therapeutically including to processes us various allow in caspase- might it a and in academic manipulate manner themselves of to apoptosis-proficient kill solely contributors cells being both independent how beyond major understanding in such, be interest, As forms death settings. might Non-apoptotic -deficient death cell should dissected. cell execution be physiological of programmed to mechanisms effects of basic differing the allow of understanding COMMENTARY 2142 A. Ashkenazi, and S. Biton, H. E. Baehrecke, and L. D. Berry, D. Sanchis, and X. J. Comella, M., Ballester, M., Llovera, J., Zhang, N., Bahi, Youle, and F. Cecconi, C., J. Sharpe, M., Karbowski, B., Gaume, D., Arnoult, References 12 after release for PMC in Deposited grants Health. and of Hospital), months. Research Institutes Children’s National Jude the fellowship. (St. from long-term ALSAC EMBO by an supported Society of is recipient Royal and D.G. the a is Union is G.I. European and Fellow. Society, Research Counci, Royal University Research the Sciences from Biological and grants Biotechnology the by supported is S.T. Funding interests. competing no declare authors The interests Competing disease. autoimmune hi .M,Rtr .W n eie B. Levine, and W. S. and Ryter, M. M., A. Guildford, Choi, D., T. Ray, R., Genga, D., Moquin, S., Challa, S., Y. Zheng, W., Cho, Li, C., Yang, Y., Song, T., W. He, D., Huang, J., Ren, W., Li, X., Chen, egbkn . ik .L n oko,B T. B. Cookson, and L. S. Fink, T., Bergsbaken, T. B. Cookson, and T. Bergsbaken, S. Fulda, and S. Cristofanon, F., Basit, un,D,L,W tal. et W. Li, caspase-independent D., Huang, and necrotic a through occur can pathway. death cell Interdigital mammalian death. of in pathways M. death S. Hedrick, cell programmed regulates homolog) development. (CED-4 Apaf1 necroptosis. TNF-induced for required is G. protein Z. Liu, and G. inhibition. L. mTOR to survival al. et enabling S. 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Journal of Cell Science clan .R,Bre,T n a,T W. T. Mak, and T. Berger, R., D. McIlwain, asmr,H,Siiu . haa . aaaa . ciaa .and Y. Uchiyama, A., Kawahara, Y., Ohsawa, Y., Shimizu, H., Matsumura, atnu . eahr . se,R,Atnsn . Andre B., Antonsson, R., Eskes, S., Desagher, I., Martinou, P. S. Cullen, and P., M. C. Juin, Henry, J., F., S. Gautier, Martin, C., J. Rain, A., Criollo, G., Toumelin, Le C., M. Maiuri, Lu B. and Levine, H. and R. Kessin, G. P., Kroemer, G. Otto, F., M. Luciani, C., and Roisin-Bouffay, A., R. Kosta, D. L. K. Green, Rock, G., and H. Hoppe, Kono, M., J. Herndon, E., J. Ricci, H., Kazama, Daley-Bauer, D., Livingston-Rosanoff, B., A. Long, W., J. Upton, J., W. Kaiser, A., Hochreiter-Hufford, M., Y. Shim, K., A. Sharma, A., Kadl, J., I. Juncadella, COMMENTARY u,S,Gri-rnii,M,Za,R,Pr,C,Th .P,Sdq .and O. Sadiq, P., P. Toh, C., Puri, R., Zhao, M., Garcia-Arencibia, S., Luo, C. D. Rubinsztein, and S. L., Luo, Zhang, V., Ginet, Y., Wei, Jr, M., R. 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Journal of Cell Science at .W,Oes,A,Qaao . iat,S,Hle,M,Wn,R,Karvela, R., Wang, M., Haller, S., Milasta, G., Quarato, A., Oberst, W., S. Tait, po,J . asr .J n oasi .S. E. Mocarski, and J. W. Kaiser, W., J. Upton, F., Neipel, E., Meinl, H., Fickenscher, K., Hofmann, P., Schneider, M., Thome, F., Wallberg, C., Langlais, M., J. Broemer, S. M., Darding, Martin, K., and Bianchi, P. T., Tenev, S. Cullen, C., R. Taylor, Mun S., Connell, L., Bouchier-Hayes, F., Llambi, J., M. Parsons, W., S. Tait, R. Liu, D. J., Green, Yan, and L., W. Wang, S. D., Tait, Liao, S., Chen, S., He, Z., Wang, H., Wang, L., W., Sun, S. Ember, M., Mazzon, C., Motes, de Maluquer T., C. Benfield, L., G. Smith, hmz,S,Knsk,T,Mzsia . iua . rkw-oaah,S., Arakawa-Kobayashi, T., Mizuta, N., Mizushima, T., Kanaseki, S., Shimizu, W. Jacob, R., Beyaert, B., Vanhaesebroeck, C., A. Bakker, K., Schulze-Osthoff, COMMENTARY 2144 S. M. Deshmukh, E. and E. Mocarski, A. Vaughn, and J. W. Kaiser, W., J. 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