KEGG   PATHWAY: mlx04613
Entry
mlx04613                    Pathway                                
Name
Neutrophil extracellular trap formation - Mirounga leonina (Southern elephant seal)
Description
Neutrophils play a central role in innate immune defense. One of the mechanisms of neutrophil action is the formation of neutrophil extracellular traps (NETs), the extracellular structures composed of chromatin coated with histones, proteases and granular and cytosolic proteins that help catch and kill microorganisms. NETs are formed by a process known as "NETosis" that can be triggered by microorganisms and endogenous stimuli, such as damage-associated molecular patterns and immune complexes, and involves activation in most cases of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, which produces reactive oxygen species (ROS). Recent study has reported that there are two different mechanisms of NETosis, including a lytic NETosis and a vital NETosis. Lytic NETosis begins with nuclear delobulation and the disassembly of the nuclear envelope and continues with loss of cellular polarization, chromatin decondensation and plasma membrane rupture. Vital NETosis can occur independently of cell death and involves the secreted expulsion of nuclear chromatin that is accompanied by the release of granule proteins through degranulation.
Class
Organismal Systems; Immune system
Pathway map
mlx04613  Neutrophil extracellular trap formation
mlx04613

Organism
Mirounga leonina (Southern elephant seal) [GN:mlx]
Gene
117997488  [KO:K11253]
117997489  [KO:K11251]
117997490  [KO:K11252]
117997491  [KO:K11254]
117997520  [KO:K11252]
117997522  [KO:K11251]
117997523  [KO:K11252]
117997524  [KO:K11252]
117997526  [KO:K11254]
117997530  [KO:K11253]
117997531  [KO:K11253]
117997742  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
117997743  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
117997744  HDAC10; polyamine deacetylase HDAC10 isoform X1 [KO:K18671] [EC:3.5.1.98]
117997993  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
117998197  C5AR1; C5a anaphylatoxin chemotactic receptor 1 [KO:K04010]
117998311  [KO:K04173]
117998715  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
117998727  NCF4; neutrophil cytosol factor 4 isoform X1 [KO:K08012]
117999123  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
117999316  ACTB; actin, cytoplasmic 1 [KO:K05692]
117999338  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
117999511  NCF1; neutrophil cytosol factor 1 [KO:K08011]
117999558  ITGAM; integrin alpha-M isoform X1 [KO:K06461]
117999594  ITGAL; integrin alpha-L isoform X1 [KO:K05718]
117999637  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
117999826  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
117999961  GP1BA; platelet glycoprotein Ib alpha chain [KO:K06261]
118000274  [KO:K11253]
118000276  [KO:K11252]
118000279  [KO:K11251]
118000280  [KO:K11251]
118000281  [KO:K11252]
118000388  [KO:K11254]
118000550  HDAC2; histone deacetylase 2 isoform X1 [KO:K06067] [EC:3.5.1.98]
118001095  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
118001265  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
118001330  MAP3K7; mitogen-activated protein kinase kinase kinase 7 isoform X1 [KO:K04427] [EC:2.7.11.25]
118002024  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118003092  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
118003321  AQP9; aquaporin-9 isoform X1 [KO:K09877]
118003336  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
118003492  CTSG; cathepsin G [KO:K01319] [EC:3.4.21.20]
118003860  [KO:K11251]
118003861  [KO:K11251]
118004424  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
118004524  [KO:K05862]
118004882  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
118004908  C3; complement C3 [KO:K03990]
118005110  CAMP; cathelicidin antimicrobial peptide [KO:K13916]
118005292  HDAC11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
118005404  [KO:K01327] [EC:3.4.21.37]
118005431  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
118005702  ATG7; ubiquitin-like modifier-activating enzyme ATG7 isoform X1 [KO:K08337]
118006042  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
118006556  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
118007649  [KO:K10802]
118008586  [KO:K11251]
118008916  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
118009146  [KO:K21421] [EC:1.-.-.-]
118009539  HMGB1; high mobility group protein B1 [KO:K10802]
118009792  [KO:K11253]
118009917  VDAC3; voltage-dependent anion-selective channel protein 3 isoform X1 [KO:K15041]
118010066  SLC25A4; ADP/ATP translocase 1 [KO:K05863]
118010082  HDAC6; histone deacetylase 6 [KO:K11407] [EC:3.5.1.98]
118010416  CLCN5; H(+)/Cl(-) exchange transporter 5 [KO:K05012]
118011244  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
118011247  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
118011463  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
118011488  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
118011879  HDAC4; histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
118012331  HAT1; histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
118012355  SLC25A5; ADP/ATP translocase 2 [KO:K05863]
118012526  [KO:K15041]
118012577  [KO:K10802]
118013015  [KO:K11253]
118013165  [KO:K04394] [EC:3.4.22.57 3.4.22.64]
118014023  FCGR3A; low affinity immunoglobulin gamma Fc region receptor III-A isoform X1 [KO:K06463]
118014262  CR1L; complement component receptor 1-like protein [KO:K04011]
118014374  NCF2; neutrophil cytosol factor 2 isoform X1 [KO:K08010]
118014500  SELP; P-selectin isoform X1 [KO:K06496]
118014553  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118014995  [KO:K06067] [EC:3.5.1.98]
118015271  GSDMD; gasdermin-D isoform X1 [KO:K20917]
118015997  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
118016059  RELA; transcription factor p65 [KO:K04735]
118016482  [KO:K11252]
118016634  VDAC1; voltage-dependent anion-selective channel protein 1 [KO:K05862]
118016660  [KO:K11251]
118016741  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
118016863  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
118017747  C5; complement C5 [KO:K03994]
118017761  TLR4; toll-like receptor 4 isoform X1 [KO:K10160]
118018155  [KO:K04392]
118018290  [KO:K11251]
118018590  SELPLG; P-selectin glycoprotein ligand 1 [KO:K06544]
118019027  [KO:K11251]
118019468  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
118019746  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
118019949  PADI4; protein-arginine deiminase type-4 isoform X1 [KO:K24669]
118020008  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
118020028  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118020839  HDAC9; histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
118021936  VDAC2; voltage-dependent anion-selective channel protein 2 [KO:K15040]
118022163  CLCN3; H(+)/Cl(-) exchange transporter 3 isoform X1 [KO:K05012]
118022199  PPIF; peptidyl-prolyl cis-trans isomerase F, mitochondrial [KO:K09565] [EC:5.2.1.8]
118022221  FGB; fibrinogen beta chain isoform X1 [KO:K03904]
118022230  TLR2; toll-like receptor 2 [KO:K10159]
118022338  SLC25A31; ADP/ATP translocase 4 [KO:K05863]
118022438  FGG; fibrinogen gamma chain isoform X1 [KO:K03905]
118022440  FGA; fibrinogen alpha chain [KO:K03903]
118022538  [KO:K10159]
118022658  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118023475  [KO:K08009]
118023528  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
118024176  ACTG1; actin, cytoplasmic 2 [KO:K05692]
118024261  [KO:K11253]
118024347  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
118024506  [KO:K11251]
118024967  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
118024979  ITGA2B; integrin alpha-IIb [KO:K06476]
118025032  MPO; myeloperoxidase [KO:K10789] [EC:1.11.2.2]
118025475  [KO:K11254]
118025632  [KO:K11251]
118025674  CLEC7A; C-type lectin domain family 7 member A isoform X1 [KO:K10074]
118025754  VWF; von Willebrand factor [KO:K03900]
118026032  HDAC8; histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
118026369  SYK; tyrosine-protein kinase SYK [KO:K05855] [EC:2.7.10.2]
118026668  SLC25A6; ADP/ATP translocase 3 [KO:K05863]
118026698  CLCN4; H(+)/Cl(-) exchange transporter 4 isoform X1 [KO:K05012]
118026716  TLR7; toll-like receptor 7 [KO:K05404]
118026718  TLR8; toll-like receptor 8 isoform X1 [KO:K10170]
118026791  [KO:K11252]
118026891  [KO:K11253]
118026892  [KO:K11251]
118026893  [KO:K11252]
118026894  [KO:K11252]
118026948  ITGB2; integrin beta-2 isoform X1 [KO:K06464]
118027034  [KO:K11251]
118027047  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
118027184  ITGB3; integrin beta-3 [KO:K06493]
118027195  AGER; advanced glycosylation end product-specific receptor [KO:K19722]
118027228  [KO:K11252]
118027229  [KO:K11251]
118027231  [KO:K11253]
118027236  [KO:K11253]
118027289  [KO:K11251]
118027290  [KO:K11252]
Compound
C00027  Hydrogen peroxide
C00039  DNA
C00076  Calcium cation
C00165  Diacylglycerol
C00338  Lipopolysaccharide
C00464  Mannan
C00518  Hyaluronate
C00551  beta-D-Glucan
C00704  Superoxide
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05151  12-O-Tetradecanoylphorbol 13-acetate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C11221  Formylmethionyl-leucyl-phenylalanine methyl ester
Reference
PMID:29543328
  Authors
Van Avondt K, Hartl D
  Title
Mechanisms and disease relevance of neutrophil extracellular trap formation.
  Journal
Eur J Clin Invest 48 Suppl 2:e12919 (2018)
DOI:10.1111/eci.12919
Reference
PMID:31518165
  Authors
Sorvillo N, Cherpokova D, Martinod K, Wagner DD
  Title
Extracellular DNA NET-Works With Dire Consequences for Health.
  Journal
Circ Res 125:470-488 (2019)
DOI:10.1161/CIRCRESAHA.119.314581
Reference
PMID:28990587
  Authors
Papayannopoulos V
  Title
Neutrophil extracellular traps in immunity and disease.
  Journal
Nat Rev Immunol 18:134-147 (2018)
DOI:10.1038/nri.2017.105
Reference
PMID:24837201
  Authors
Liu FC, Chuang YH, Tsai YF, Yu HP
  Title
Role of neutrophil extracellular traps following injury.
  Journal
Shock 41:491-8 (2014)
DOI:10.1097/SHK.0000000000000146
Reference
PMID:27570525
  Authors
Yang H, Biermann MH, Brauner JM, Liu Y, Zhao Y, Herrmann M
  Title
New Insights into Neutrophil Extracellular Traps: Mechanisms of Formation and Role in Inflammation.
  Journal
Front Immunol 7:302 (2016)
DOI:10.3389/fimmu.2016.00302
Reference
PMID:28983472
  Authors
Zawrotniak M, Bochenska O, Karkowska-Kuleta J, Seweryn-Ozog K, Aoki W, Ueda M, Kozik A, Rapala-Kozik M
  Title
Aspartic Proteases and Major Cell Wall Components in Candida albicans Trigger the Release of Neutrophil Extracellular Traps.
  Journal
Front Cell Infect Microbiol 7:414 (2017)
DOI:10.3389/fcimb.2017.00414
Reference
PMID:29382950
  Authors
Honda M, Kubes P
  Title
Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system.
  Journal
Nat Rev Gastroenterol Hepatol 15:206-221 (2018)
DOI:10.1038/nrgastro.2017.183
Reference
PMID:31416265
  Authors
Hamam HJ, Palaniyar N
  Title
Post-Translational Modifications in NETosis and NETs-Mediated Diseases.
  Journal
Biomolecules 9:E369 (2019)
DOI:10.3390/biom9080369
Reference
PMID:31767647
  Authors
Burgener SS, Schroder K
  Title
Neutrophil Extracellular Traps in Host Defense.
  Journal
Cold Spring Harb Perspect Biol 12:a037028 (2020)
DOI:10.1101/cshperspect.a037028
Reference
PMID:33202203
  Authors
Vorobjeva NV, Chernyak BV
  Title
NETosis: Molecular Mechanisms, Role in Physiology and Pathology.
  Journal
Biochemistry (Mosc) 85:1178-1190 (2020)
DOI:10.1134/S0006297920100065
Reference
PMID:31416173
  Authors
Ravindran M, Khan MA, Palaniyar N
  Title
Neutrophil Extracellular Trap Formation: Physiology, Pathology, and Pharmacology.
  Journal
Biomolecules 9:E365 (2019)
DOI:10.3390/biom9080365
Reference
PMID:28267716
  Authors
Jorch SK, Kubes P
  Title
An emerging role for neutrophil extracellular traps in noninfectious disease.
  Journal
Nat Med 23:279-287 (2017)
DOI:10.1038/nm.4294
Reference
PMID:31342866
  Authors
Goggs R, Jeffery U, LeVine DN, Li RHL
  Title
Neutrophil-Extracellular Traps, Cell-Free DNA, and Immunothrombosis in Companion Animals: A Review.
  Journal
Vet Pathol 57:6-23 (2020)
DOI:10.1177/0300985819861721
Reference
PMID:27876233
  Authors
Kim SJ, Jenne CN
  Title
Role of platelets in neutrophil extracellular trap (NET) production and tissue injury.
  Journal
Semin Immunol 28:546-554 (2016)
DOI:10.1016/j.smim.2016.10.013
Reference
PMID:29572545
  Authors
de Bont CM, Boelens WC, Pruijn GJM
  Title
NETosis, complement, and coagulation: a triangular relationship.
  Journal
Cell Mol Immunol 16:19-27 (2019)
DOI:10.1038/s41423-018-0024-0
Reference
PMID:31129510
  Authors
Zawrotniak M, Bartnicka D, Rapala-Kozik M
  Title
UVA and UVB radiation induce the formation of neutrophil extracellular traps by human polymorphonuclear cells.
  Journal
J Photochem Photobiol B 196:111511 (2019)
DOI:10.1016/j.jphotobiol.2019.111511
Reference
PMID:21293492
  Authors
Remijsen Q, Kuijpers TW, Wirawan E, Lippens S, Vandenabeele P, Vanden Berghe T
  Title
Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality.
  Journal
Cell Death Differ 18:581-8 (2011)
DOI:10.1038/cdd.2011.1
Reference
PMID:23819131
  Authors
Zawrotniak M, Rapala-Kozik M
  Title
Neutrophil extracellular traps (NETs) - formation and implications.
  Journal
Acta Biochim Pol 60:277-84 (2013)
Reference
PMID:28373871
  Authors
Rosales C
  Title
Fcgamma Receptor Heterogeneity in Leukocyte Functional Responses.
  Journal
Front Immunol 8:280 (2017)
DOI:10.3389/fimmu.2017.00280
Reference
PMID:25716722
  Authors
Vorobjeva NV, Pinegin BV
  Title
Neutrophil extracellular traps: mechanisms of formation and role in health and disease.
  Journal
Biochemistry (Mosc) 79:1286-96 (2014)
DOI:10.1134/S0006297914120025
Reference
PMID:28220120
  Authors
Delgado-Rizo V, Martinez-Guzman MA, Iniguez-Gutierrez L, Garcia-Orozco A, Alvarado-Navarro A, Fafutis-Morris M
  Title
Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview.
  Journal
Front Immunol 8:81 (2017)
DOI:10.3389/fimmu.2017.00081
Reference
PMID:30023352
  Authors
Fonseca Z, Diaz-Godinez C, Mora N, Aleman OR, Uribe-Querol E, Carrero JC, Rosales C
  Title
Entamoeba histolytica Induce Signaling via Raf/MEK/ERK for Neutrophil Extracellular Trap (NET) Formation.
  Journal
Front Cell Infect Microbiol 8:226 (2018)
DOI:10.3389/fcimb.2018.00226
Reference
PMID:27923601
  Authors
Agraz-Cibrian JM, Giraldo DM, Mary FM, Urcuqui-Inchima S
  Title
Understanding the molecular mechanisms of NETs and their role in antiviral innate immunity.
  Journal
Virus Res 228:124-133 (2017)
DOI:10.1016/j.virusres.2016.11.033
Reference
PMID:27698656
  Authors
Schonrich G, Raftery MJ
  Title
Neutrophil Extracellular Traps Go Viral.
  Journal
Front Immunol 7:366 (2016)
DOI:10.3389/fimmu.2016.00366
Reference
PMID:22817992
  Authors
Saitoh T, Komano J, Saitoh Y, Misawa T, Takahama M, Kozaki T, Uehata T, Iwasaki H, Omori H, Yamaoka S, Yamamoto N, Akira S
  Title
Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1.
  Journal
Cell Host Microbe 12:109-16 (2012)
DOI:10.1016/j.chom.2012.05.015
Reference
PMID:29908538
  Authors
Kumar S, Gupta E, Kaushik S, Jyoti A
  Title
Neutrophil Extracellular Traps: Formation and Involvement in Disease Progression.
  Journal
Iran J Allergy Asthma Immunol 17:208-220 (2018)
Related
pathway
mlx04010  MAPK signaling pathway
mlx04020  Calcium signaling pathway
mlx04140  Autophagy - animal
mlx04151  PI3K-Akt signaling pathway
mlx04610  Complement and coagulation cascades
mlx04611  Platelet activation
mlx04620  Toll-like receptor signaling pathway
mlx04621  NOD-like receptor signaling pathway
mlx04666  Fc gamma R-mediated phagocytosis
KO pathway
ko04613   

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