KEGG PATHWAY: ko04217

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

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