KEGG   PATHWAY: ko04217
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
ko04217

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:1.16.3.2]
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
K20703  FAS-associated factor 1
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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  Authors
Guo H, Kaiser WJ
  Title
ESCRTing Necroptosis.
  Journal
Cell 169:186-187 (2017)
DOI:10.1016/j.cell.2017.03.030
Reference
  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
  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
  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
  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
  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
Related
pathway
ko00250  Alanine, aspartate and glutamate metabolism
ko04210  Apoptosis
ko04668  TNF signaling pathway
ko04922  Glucagon signaling pathway
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