ENTRY ko04217 Pathway NAME Necroptosis DESCRIPTION Necroptosis is a programmed form of necrosis. It can be initiated by different stimuli, such as tumor necrosis factor (TNF), TNF-related apoptosis-inducing ligand (TRAIL), Fas ligand (FasL), interferon (IFN), LPS, viral DNA or RNA, DNA-damage agent and requires the kinase activity of receptor-interacting protein 1 (RIPK1) and RIPK3. Its execution involves ROS generation, calcium overload, the opening of the mitochondrial permeability transition pore, mitochondrial fission, inflammatory response and chromatinolysis. Necroptosis participates in many pathogenesis of diseases, including neurological diseases, retinal disorders, acute kidney injury, inflammatory diseases and microbial infections. CLASS Cellular Processes; Cell growth and death PATHWAY_MAP ko04217 Necroptosis ORTHOLOGY K03156 tumor necrosis factor superfamily, member 2 K03158 tumor necrosis factor receptor superfamily member 1A K03171 tumor necrosis factor receptor type 1-associated DEATH domain protein K03173 TNF receptor-associated factor 2 [EC:2.3.2.27] K09849 TNF receptor-associated factor 5 K02861 receptor-interacting serine/threonine-protein kinase 1 [EC:2.7.11.1] K16060 baculoviral IAP repeat-containing protein 2/3 K04725 E3 ubiquitin-protein ligase XIAP [EC:2.3.2.27] K10630 RanBP-type and C3HC4-type zinc finger-containing protein 1 [EC:2.3.2.31] K11974 E3 ubiquitin-protein ligase RNF31 [EC:2.3.2.31] K20894 shank-associated RH domain-interacting protein K17595 spermatogenesis-associated protein 2 K08601 ubiquitin carboxyl-terminal hydrolase CYLD [EC:3.4.19.12] K02373 FAS-associated death domain protein K04398 caspase 8 [EC:3.4.22.61] K04724 CASP8 and FADD-like apoptosis regulator K08847 receptor-interacting serine/threonine-protein kinase 3 [EC:2.7.11.1] K21421 NADPH oxidase 2 [EC:1.-.-.-] K04515 calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17] K05863 solute carrier family 25 (mitochondrial adenine nucleotide translocator), member 4/5/6/31 K05864 peptidyl-prolyl isomerase D [EC:5.2.1.8] K05862 voltage-dependent anion channel protein 1 K15040 voltage-dependent anion channel protein 2 K15041 voltage-dependent anion channel protein 3 K00261 glutamate dehydrogenase (NAD(P)+) [EC:1.4.1.3] K01915 glutamine synthetase [EC:6.3.1.2] K00688 glycogen phosphorylase [EC:2.4.1.1] K04440 mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24] K00522 ferritin heavy chain [EC:1.16.3.1] K13625 ferritin light chain K16342 cytosolic phospholipase A2 [EC:3.1.1.4] K00460 arachidonate 15-lipoxygenase [EC:1.13.11.33] K01367 calpain-1 [EC:3.4.22.52] K03853 calpain-2 [EC:3.4.22.53] K12350 sphingomyelin phosphodiesterase [EC:3.1.4.12] K08849 mixed lineage kinase domain-like [EC:2.7.11.1] K15637 serine/threonine-protein phosphatase PGAM5 [EC:3.1.3.16] K17065 dynamin 1-like protein [EC:3.6.5.5] K12800 NACHT, LRR and PYD domains-containing protein 3 K12799 apoptosis-associated speck-like protein containing a CARD K01370 caspase 1 [EC:3.4.22.36] K04519 interleukin 1 beta K12191 charged multivesicular body protein 2A K12192 charged multivesicular body protein 2B K12193 charged multivesicular body protein 3 K12194 charged multivesicular body protein 4A/B K24782 charged multivesicular body protein 4C K12195 charged multivesicular body protein 6 K12196 vacuolar protein-sorting-associated protein 4 K12197 charged multivesicular body protein 1 K12198 charged multivesicular body protein 5 K15053 charged multivesicular body protein 7 K04982 transient receptor potential cation channel subfamily M member 7 [EC:2.7.11.1] K04383 interleukin 1 alpha K12967 interleukin 33 K10802 high mobility group protein B1 K04721 tumor necrosis factor ligand superfamily member 10 K04722 tumor necrosis factor receptor superfamily member 10A/B K04389 tumor necrosis factor ligand superfamily member 6 K04390 tumor necrosis factor receptor superfamily member 6 K05414 interferon alpha K05415 interferon beta K04687 interferon gamma K05130 interferon receptor 1 K05131 interferon receptor 2 K05132 interferon gamma receptor 1 K05133 interferon gamma receptor 2 K11217 Janus kinase 1 [EC:2.7.10.2] K04447 Janus kinase 2 [EC:2.7.10.2] K11218 Janus kinase 3 [EC:2.7.10.2] K11219 non-receptor tyrosine-protein kinase TYK2 [EC:2.7.10.2] K11220 signal transducer and activator of transcription 1 K11221 signal transducer and activator of transcription 2 K04692 signal transducer and activator of transcription 3 K11222 signal transducer and activator of transcription 4 K11223 signal transducer and activator of transcription 5A K11224 signal transducer and activator of transcription 5B K11225 signal transducer and activator of transcription 6 K04693 interferon regulatory factor 9 K16195 eukaryotic translation initiation factor 2-alpha kinase 2 [EC:2.7.11.1] K10160 toll-like receptor 4 K05409 TRIF-related adaptor molecule K05842 toll-like receptor adapter molecule 1 K05401 toll-like receptor 3 K12965 Z-DNA binding protein 1 K21634 ubiquitin carboxyl-terminal hydrolase 21 [EC:3.4.19.12] K14381 sequestosome 1 K04079 molecular chaperone HtpG K11859 tumor necrosis factor, alpha-induced protein 3 [EC:3.4.19.12] K24070 poly [ADP-ribose] polymerase 1 [EC:2.4.2.30] K04726 BH3 interacting domain death agonist K02159 apoptosis regulator BAX K04727 apoptosis-inducing factor 1 [EC:1.-.-.-] K11251 histone H2A K03767 peptidyl-prolyl cis-trans isomerase A (cyclophilin A) [EC:5.2.1.8] K02161 apoptosis regulator Bcl-2 COMPOUND C00002 ATP C00027 Hydrogen peroxide C00076 Calcium cation C00195 N-Acylsphingosine C00219 Arachidonate C00305 Magnesium cation C00319 Sphingosine C00550 Sphingomyelin C14592 N-Methyl-N'-nitro-N-nitrosoguanidine C16844 Hydroxyl radical REFERENCE PMID:20823910 AUTHORS Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G TITLE Molecular mechanisms of necroptosis: an ordered cellular explosion. JOURNAL Nat Rev Mol Cell Biol 11:700-14 (2010) DOI:10.1038/nrm2970 REFERENCE PMID:26008591 AUTHORS Brenner D, Blaser H, Mak TW TITLE Regulation of tumour necrosis factor signalling: live or let die. JOURNAL Nat Rev Immunol 15:362-74 (2015) DOI:10.1038/nri3834 REFERENCE PMID:26775689 AUTHORS Conrad M, Angeli JP, Vandenabeele P, Stockwell BR TITLE Regulated necrosis: disease relevance and therapeutic opportunities. JOURNAL Nat Rev Drug Discov 15:348-66 (2016) DOI:10.1038/nrd.2015.6 REFERENCE PMID:24129419 AUTHORS Ofengeim D, Yuan J TITLE Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. JOURNAL Nat Rev Mol Cell Biol 14:727-36 (2013) DOI:10.1038/nrm3683 REFERENCE PMID:27158445 AUTHORS Murphy JM, Vince JE TITLE Post-translational control of RIPK3 and MLKL mediated necroptotic cell death. JOURNAL F1000Res 4:F1000 Faculty Rev-1297 (2015) DOI:10.12688/f1000research.7046.1 REFERENCE PMID:24452471 AUTHORS Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P TITLE Regulated necrosis: the expanding network of non-apoptotic cell death pathways. JOURNAL Nat Rev Mol Cell Biol 15:135-47 (2014) DOI:10.1038/nrm3737 REFERENCE PMID:27368376 AUTHORS Dondelinger Y, Hulpiau P, Saeys Y, Bertrand MJ, Vandenabeele P TITLE An evolutionary perspective on the necroptotic pathway. JOURNAL Trends Cell Biol 26:721-32 (2016) DOI:10.1016/j.tcb.2016.06.004 REFERENCE PMID:27746097 AUTHORS Thapa RJ, Ingram JP, Ragan KB, Nogusa S, Boyd DF, Benitez AA, Sridharan H, Kosoff R, Shubina M, Landsteiner VJ, Andrake M, Vogel P, Sigal LJ, tenOever BR, Thomas PG, Upton JW, Balachandran S TITLE DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death. JOURNAL Cell Host Microbe 20:674-681 (2016) DOI:10.1016/j.chom.2016.09.014 REFERENCE PMID:27984721 AUTHORS Yuan J, Najafov A, Py BF TITLE Roles of Caspases in Necrotic Cell Death. JOURNAL Cell 167:1693-1704 (2016) DOI:10.1016/j.cell.2016.11.047 REFERENCE PMID:28138137 AUTHORS Jorgensen I, Rayamajhi M, Miao EA TITLE Programmed cell death as a defence against infection. JOURNAL Nat Rev Immunol 17:151-164 (2017) DOI:10.1038/nri.2016.147 REFERENCE PMID:20354226 AUTHORS Vandenabeele P, Declercq W, Van Herreweghe F, Vanden Berghe T TITLE The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. JOURNAL Sci Signal 3:re4 (2010) DOI:10.1126/scisignal.3115re4 REFERENCE PMID:22075985 AUTHORS Vanlangenakker N, Vanden Berghe T, Vandenabeele P TITLE Many stimuli pull the necrotic trigger, an overview. JOURNAL Cell Death Differ 19:75-86 (2012) DOI:10.1038/cdd.2011.164 REFERENCE PMID:23913919 AUTHORS Moriwaki K, Chan FK TITLE RIP3: a molecular switch for necrosis and inflammation. JOURNAL Genes Dev 27:1640-9 (2013) DOI:10.1101/gad.223321.113 REFERENCE PMID:25146926 AUTHORS Humphries F, Yang S, Wang B, Moynagh PN TITLE RIP kinases: key decision makers in cell death and innate immunity. JOURNAL Cell Death Differ 22:225-36 (2015) DOI:10.1038/cdd.2014.126 REFERENCE PMID:28126382 AUTHORS Wegner KW, Saleh D, Degterev A TITLE Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis. JOURNAL Trends Pharmacol Sci 38:202-225 (2017) DOI:10.1016/j.tips.2016.12.005 REFERENCE PMID:27545878 AUTHORS Kupka S, De Miguel D, Draber P, Martino L, Surinova S, Rittinger K, Walczak H TITLE SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes. JOURNAL Cell Rep 16:2271-80 (2016) DOI:10.1016/j.celrep.2016.07.086 REFERENCE PMID:27219062 AUTHORS Goodall ML, Fitzwalter BE, Zahedi S, Wu M, Rodriguez D, Mulcahy-Levy JM, Green DR, Morgan M, Cramer SD, Thorburn A TITLE The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis. JOURNAL Dev Cell 37:337-49 (2016) DOI:10.1016/j.devcel.2016.04.018 REFERENCE PMID:19910467 AUTHORS Xu G, Tan X, Wang H, Sun W, Shi Y, Burlingame S, Gu X, Cao G, Zhang T, Qin J, Yang J TITLE Ubiquitin-specific peptidase 21 inhibits tumor necrosis factor alpha-induced nuclear factor kappaB activation via binding to and deubiquitinating receptor-interacting protein 1. JOURNAL J Biol Chem 285:969-78 (2010) DOI:10.1074/jbc.M109.042689 REFERENCE PMID:26971869 AUTHORS Jacobsen AV, Silke J TITLE The importance of being chaperoned: HSP90 and necroptosis. JOURNAL Cell Chem Biol 23:205-7 (2016) DOI:10.1016/j.chembiol.2016.02.003 REFERENCE PMID:25988900 AUTHORS Gurung P, Man SM, Kanneganti TD TITLE A20 is a regulator of necroptosis. JOURNAL Nat Immunol 16:596-7 (2015) DOI:10.1038/ni.3174 REFERENCE PMID:28025046 AUTHORS Feng N, Anderson ME TITLE CaMKII is a nodal signal for multiple programmed cell death pathways in heart. JOURNAL J Mol Cell Cardiol 103:102-109 (2017) DOI:10.1016/j.yjmcc.2016.12.007 REFERENCE PMID:19696789 AUTHORS Zhivotovsky B, Galluzzi L, Kepp O, Kroemer G TITLE Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machinery. JOURNAL Cell Death Differ 16:1419-25 (2009) DOI:10.1038/cdd.2009.118 REFERENCE PMID:23898178 AUTHORS Thapa RJ, Nogusa S, Chen P, Maki JL, Lerro A, Andrake M, Rall GF, Degterev A, Balachandran S TITLE Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. JOURNAL Proc Natl Acad Sci U S A 110:E3109-18 (2013) DOI:10.1073/pnas.1301218110 REFERENCE PMID:21576359 AUTHORS Thapa RJ, Basagoudanavar SH, Nogusa S, Irrinki K, Mallilankaraman K, Slifker MJ, Beg AA, Madesh M, Balachandran S TITLE NF-kappaB protects cells from gamma interferon-induced RIP1-dependent necroptosis. JOURNAL Mol Cell Biol 31:2934-46 (2011) DOI:10.1128/MCB.05445-11 REFERENCE PMID:24565922 AUTHORS Sridharan H, Upton JW TITLE Programmed necrosis in microbial pathogenesis. JOURNAL Trends Microbiol 22:199-207 (2014) DOI:10.1016/j.tim.2014.01.005 REFERENCE PMID:21738214 AUTHORS Cabon L, Galan-Malo P, Bouharrour A, Delavallee L, Brunelle-Navas MN, Lorenzo HK, Gross A, Susin SA TITLE BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation. JOURNAL Cell Death Differ 19:245-56 (2012) DOI:10.1038/cdd.2011.91 REFERENCE PMID:20697198 AUTHORS Baritaud M, Boujrad H, Lorenzo HK, Krantic S, Susin SA TITLE Histone H2AX: The missing link in AIF-mediated caspase-independent programmed necrosis. JOURNAL Cell Cycle 9:3166-73 (2010) DOI:10.4161/cc.9.16.12887 REFERENCE PMID:28279333 AUTHORS Upton JW, Kaiser WJ TITLE DAI Another Way: Necroptotic Control of Viral Infection. JOURNAL Cell Host Microbe 21:290-293 (2017) DOI:10.1016/j.chom.2017.01.016 REFERENCE PMID:26086143 AUTHORS Silke J, Rickard JA, Gerlic M TITLE The diverse role of RIP kinases in necroptosis and inflammation. JOURNAL Nat Immunol 16:689-97 (2015) DOI:10.1038/ni.3206 REFERENCE PMID:28388403 AUTHORS Guo H, Kaiser WJ TITLE ESCRTing Necroptosis. JOURNAL Cell 169:186-187 (2017) DOI:10.1016/j.cell.2017.03.030 REFERENCE PMID:28388412 AUTHORS Gong YN, Guy C, Olauson H, Becker JU, Yang M, Fitzgerald P, Linkermann A, Green DR TITLE ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences. JOURNAL Cell 169:286-300.e16 (2017) DOI:10.1016/j.cell.2017.03.020 REFERENCE PMID:27999433 AUTHORS Petrie EJ, Hildebrand JM, Murphy JM TITLE Insane in the membrane: a structural perspective of MLKL function in necroptosis. JOURNAL Immunol Cell Biol 95:152-159 (2017) DOI:10.1038/icb.2016.125 REFERENCE PMID:24316671 AUTHORS Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, Ward Y, Wu LG, Liu ZG TITLE Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. JOURNAL Nat Cell Biol 16:55-65 (2014) DOI:10.1038/ncb2883 REFERENCE PMID:25693118 AUTHORS Lawlor KE, Khan N, Mildenhall A, Gerlic M, Croker BA, D'Cruz AA, Hall C, Kaur Spall S, Anderton H, Masters SL, Rashidi M, Wicks IP, Alexander WS, Mitsuuchi Y, Benetatos CA, Condon SM, Wong WW, Silke J, Vaux DL, Vince JE TITLE RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. JOURNAL Nat Commun 6:6282 (2015) DOI:10.1038/ncomms7282 REFERENCE PMID:27974745 AUTHORS Shlomovitz I, Zargrian S, Gerlic M TITLE Mechanisms of RIPK3-induced inflammation. JOURNAL Immunol Cell Biol 95:166-172 (2017) DOI:10.1038/icb.2016.124 REL_PATHWAY ko00250 Alanine, aspartate and glutamate metabolism ko04210 Apoptosis ko04668 TNF signaling pathway ko04922 Glucagon signaling pathway ///