KEGG   PATHWAY: hsa05135
Entry
hsa05135                    Pathway                                
Name
Yersinia infection - Homo sapiens (human)
Description
Pathogenic Yersinia injects virulent Yersinia outer proteins (Yops) into the host cell through a type three secretion system (T3SS) to express its pathogenicity. Through inactivation of small GTPases by YopT protease, YopE GTPase-activating protein, and YpkA/YopO sequestration of GDP-bound small GTPases, Yersinia prevents its uptake by phagocytic cells and disrupts the actin cytoskeleton. YopH phosphatase shuts down phagocytosis by dephosphorylating key host proteins as well as suppresses T cell activation. Yersinia induces macrophage pyroptosis via YopB/YopD activation of canonical and noncanonical inflammasomes and YopT/YopE-mediated activation of pyrin. These effects are counteracted by YopK and YopM. YopP/J is a member of an ubiquitin-like protein cysteine protease family and simultaneously targets signaling components of the MAPK and NF-kappaB signaling pathways following activation of Toll-like receptor4 to inhibit production of proinflammatory cytokines.
Class
Human Diseases; Infectious disease: bacterial
Pathway map
hsa05135  Yersinia infection
hsa05135

Network
  Element
N00859  Yersinia YopP/J to TLR2/4-NFKB signaling pathway
N00862  Yersinia YopP/J to TLR2/4-MAPK signaling pathway
N00863  Yersinia YopM to NLRP3 Inflammasome signaling pathway
N00864  Yersinia YopK to NLRP3 Inflammasome signaling pathway
N00865  Yersinia YopK to NLRC4 Inflammasome signaling pathway
N00866  Yersinia YopM to Pyrin Inflammasome signaling pathway
N01098  Yersinia YopT to ITGA/B-RhoGEF-RhoA signaling pathway
N01099  Yersinia YopE to RhoA signaling pathway
N01100  Yersinia YopE to ITGA/B-RHOG-RAC signaling pathway
N01101  Yersinia YopT to ITGA/B-RHOG-RAC signaling pathway
N01102  Yersinia YopE to ITGA/B-RHOG-RAC signaling pathway
N01103  Yersinia YpkA to IGG-FCGR-RAC signaling pathway
N01105  Yersinia YpkA to LPA-GNAQ-RhoA signaling pathway
N01107  Yersinia YopH to TCR-NFAT signaling pathway
N01108  Yersinia YopH to TCR-NFAT signaling pathway
N01109  Yersinia YopH to ITGA/B-FAK-RAC signaling pathway
N01110  Yersinia YopH to ITGA/B-FAK-RAC signaling pathway
N01111  Yersinia YopH to ITGA/B-FAK-RAC signaling pathway
Disease
H00298  Yersiniosis
Organism
Homo sapiens (human) [GN:hsa]
Gene
2335  FN1; fibronectin 1 [KO:K05717]
3676  ITGA4; integrin subunit alpha 4 [KO:K06483]
3678  ITGA5; integrin subunit alpha 5 [KO:K06484]
3688  ITGB1; integrin subunit beta 1 [KO:K05719]
391  RHOG; ras homolog family member G [KO:K07863]
6714  SRC; SRC proto-oncogene, non-receptor tyrosine kinase [KO:K05704] [EC:2.7.10.2]
5747  PTK2; protein tyrosine kinase 2 [KO:K05725] [EC:2.7.10.2]
2185  PTK2B; protein tyrosine kinase 2 beta [KO:K05871] [EC:2.7.10.2]
1398  CRK; CRK proto-oncogene, adaptor protein [KO:K04438]
1399  CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438]
9564  BCAR1; BCAR1 scaffold protein, Cas family member [KO:K05726]
9844  ELMO1; engulfment and cell motility 1 [KO:K12366]
63916  ELMO2; engulfment and cell motility 2 [KO:K18985]
1793  DOCK1; dedicator of cytokinesis 1 [KO:K13708]
102723407  IGH; immunoglobulin heavy variable 4-38-2-like [KO:K06856]
2212  FCGR2A; Fc gamma receptor IIa [KO:K06472]
5879  RAC1; Rac family small GTPase 1 [KO:K04392]
5880  RAC2; Rac family small GTPase 2 [KO:K07860]
5881  RAC3; Rac family small GTPase 3 [KO:K07861]
23396  PIP5K1C; phosphatidylinositol-4-phosphate 5-kinase type 1 gamma [KO:K00889] [EC:2.7.1.68]
8394  PIP5K1A; phosphatidylinositol-4-phosphate 5-kinase type 1 alpha [KO:K00889] [EC:2.7.1.68]
8395  PIP5K1B; phosphatidylinositol-4-phosphate 5-kinase type 1 beta [KO:K00889] [EC:2.7.1.68]
382  ARF6; ADP ribosylation factor 6 [KO:K07941]
8976  WASL; WASP like actin nucleation promoting factor [KO:K23612]
10097  ACTR2; actin related protein 2 [KO:K17260]
57180  ACTR3B; actin related protein 3B [KO:K18584]
653857  ACTR3C; actin related protein 3C [KO:K18584]
10096  ACTR3; actin related protein 3 [KO:K18584]
10095  ARPC1B; actin related protein 2/3 complex subunit 1B [KO:K05757]
10552  ARPC1A; actin related protein 2/3 complex subunit 1A [KO:K05757]
10109  ARPC2; actin related protein 2/3 complex subunit 2 [KO:K05758]
10094  ARPC3; actin related protein 2/3 complex subunit 3 [KO:K05756]
10093  ARPC4; actin related protein 2/3 complex subunit 4 [KO:K05755]
10092  ARPC5; actin related protein 2/3 complex subunit 5 [KO:K05754]
81873  ARPC5L; actin related protein 2/3 complex subunit 5 like [KO:K05754]
71  ACTG1; actin gamma 1 [KO:K05692]
60  ACTB; actin beta [KO:K05692]
147179  WIPF2; WAS/WASL interacting protein family member 2 [KO:K19475]
7456  WIPF1; WAS/WASL interacting protein family member 1 [KO:K19475]
644150  WIPF3; WAS/WASL interacting protein family member 3 [KO:K19475]
10458  BAIAP2; BAR/IMD domain containing adaptor protein 2 [KO:K05627]
10163  WASF2; WASP family member 2 [KO:K05748]
5829  PXN; paxillin [KO:K05760]
9815  GIT2; GIT ArfGAP 2 [KO:K12487]
8874  ARHGEF7; Rho guanine nucleotide exchange factor 7 [KO:K13710]
998  CDC42; cell division cycle 42 [KO:K04393]
7454  WAS; WASP actin nucleation promoting factor [KO:K05747]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
23365  ARHGEF12; Rho guanine nucleotide exchange factor 12 [KO:K07532]
9138  ARHGEF1; Rho guanine nucleotide exchange factor 1 [KO:K12330]
64283  ARHGEF28; Rho guanine nucleotide exchange factor 28 [KO:K21072]
387  RHOA; ras homolog family member A [KO:K04513]
6093  ROCK1; Rho associated coiled-coil containing protein kinase 1 [KO:K04514] [EC:2.7.11.1]
9475  ROCK2; Rho associated coiled-coil containing protein kinase 2 [KO:K17388] [EC:2.7.11.1]
2533  FYB1; FYN binding protein 1 [KO:K17698]
8935  SKAP2; src kinase associated phosphoprotein 2 [KO:K23471]
114548  NLRP3; NLR family pyrin domain containing 3 [KO:K12800]
58484  NLRC4; NLR family CARD domain containing 4 [KO:K12805]
5585  PKN1; protein kinase N1 [KO:K06071] [EC:2.7.11.13]
5586  PKN2; protein kinase N2 [KO:K23691] [EC:2.7.11.13]
6197  RPS6KA3; ribosomal protein S6 kinase A3 [KO:K04373] [EC:2.7.11.1]
6195  RPS6KA1; ribosomal protein S6 kinase A1 [KO:K04373] [EC:2.7.11.1]
6196  RPS6KA2; ribosomal protein S6 kinase A2 [KO:K04373] [EC:2.7.11.1]
27330  RPS6KA6; ribosomal protein S6 kinase A6 [KO:K04373] [EC:2.7.11.1]
4210  MEFV; MEFV innate immunity regulator, pyrin [KO:K12803]
3984  LIMK1; LIM domain kinase 1 [KO:K05743] [EC:2.7.11.1]
29108  PYCARD; PYD and CARD domain containing [KO:K12799]
834  CASP1; caspase 1 [KO:K01370] [EC:3.4.22.36]
3606  IL18; interleukin 18 [KO:K05482]
3553  IL1B; interleukin 1 beta [KO:K04519]
7099  TLR4; toll like receptor 4 [KO:K10160]
4615  MYD88; MYD88 innate immune signal transduction adaptor [KO:K04729]
51135  IRAK4; interleukin 1 receptor associated kinase 4 [KO:K04733] [EC:2.7.11.1]
3654  IRAK1; interleukin 1 receptor associated kinase 1 [KO:K04730] [EC:2.7.11.1]
7189  TRAF6; TNF receptor associated factor 6 [KO:K03175] [EC:2.3.2.27]
7186  TRAF2; TNF receptor associated factor 2 [KO:K03173] [EC:2.3.2.27]
10454  TAB1; TGF-beta activated kinase 1 (MAP3K7) binding protein 1 [KO:K04403]
23118  TAB2; TGF-beta activated kinase 1 (MAP3K7) binding protein 2 [KO:K04404]
6885  MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210]
1147  CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
5606  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
5608  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
6416  MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
5609  MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
148022  TICAM1; TIR domain containing adaptor molecule 1 [KO:K05842]
29110  TBK1; TANK binding kinase 1 [KO:K05410] [EC:2.7.11.10]
3661  IRF3; interferon regulatory factor 3 [KO:K05411]
7124  TNF; tumor necrosis factor [KO:K03156]
3569  IL6; interleukin 6 [KO:K05405]
3576  CXCL8; C-X-C motif chemokine ligand 8 [KO:K10030]
3456  IFNB1; interferon beta 1 [KO:K05415]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
2932  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
6347  CCL2; C-C motif chemokine ligand 2 [KO:K14624]
920  CD4; CD4 molecule [KO:K06454]
925  CD8A; CD8 subunit alpha [KO:K06458]
926  CD8B; CD8 subunit beta [KO:K06459]
927  CD8B2; CD8B family member 2 [KO:K06459]
3932  LCK; LCK proto-oncogene, Src family tyrosine kinase [KO:K05856] [EC:2.7.10.2]
7535  ZAP70; zeta chain of T cell receptor associated protein kinase 70 [KO:K07360] [EC:2.7.10.2]
27040  LAT; linker for activation of T cells [KO:K07362]
3937  LCP2; lymphocyte cytosolic protein 2 [KO:K07361]
10451  VAV3; vav guanine nucleotide exchange factor 3 [KO:K05730]
7409  VAV1; vav guanine nucleotide exchange factor 1 [KO:K05730]
7410  VAV2; vav guanine nucleotide exchange factor 2 [KO:K05730]
5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
4772  NFATC1; nuclear factor of activated T cells 1 [KO:K04446]
4773  NFATC2; nuclear factor of activated T cells 2 [KO:K17332]
4775  NFATC3; nuclear factor of activated T cells 3 [KO:K17333]
3558  IL2; interleukin 2 [KO:K05429]
3586  IL10; interleukin 10 [KO:K05443]
Compound
C00076  Calcium cation
C00338  Lipopolysaccharide
C01245  D-myo-Inositol 1,4,5-trisphosphate
C04637  1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
PMID:26981193
  Authors
Pha K, Navarro L
  Title
Yersinia type III effectors perturb host innate immune responses.
  Journal
World J Biol Chem 7:1-13 (2016)
DOI:10.4331/wjbc.v7.i1.1
Reference
PMID:29477730
  Authors
Pinaud L, Sansonetti PJ, Phalipon A
  Title
Host Cell Targeting by Enteropathogenic Bacteria T3SS Effectors.
  Journal
Trends Microbiol 26:266-283 (2018)
DOI:10.1016/j.tim.2018.01.010
Reference
PMID:19339545
  Authors
Huveneers S, Danen EH
  Title
Adhesion signaling - crosstalk between integrins, Src and Rho.
  Journal
J Cell Sci 122:1059-69 (2009)
DOI:10.1242/jcs.039446
Reference
PMID:17257058
  Authors
Angot A, Vergunst A, Genin S, Peeters N
  Title
Exploitation of eukaryotic ubiquitin signaling pathways by effectors translocated by bacterial type III and type IV secretion systems.
  Journal
PLoS Pathog 3:e3 (2007)
DOI:10.1371/journal.ppat.0030003
Reference
PMID:10785635
  Authors
Bliska JB
  Title
Yop effectors of Yersinia spp. and actin rearrangements.
  Journal
Trends Microbiol 8:205-8 (2000)
DOI:10.1016/S0966-842X(00)01738-8
Reference
PMID:15044442
  Authors
Gustavsson A, Yuan M, Fallman M
  Title
Temporal dissection of beta1-integrin signaling indicates a role for p130Cas-Crk in filopodia formation.
  Journal
J Biol Chem 279:22893-901 (2004)
DOI:10.1074/jbc.M309693200
Reference
PMID:12077360
  Authors
Bruce-Staskal PJ, Weidow CL, Gibson JJ, Bouton AH
  Title
Cas, Fak and Pyk2 function in diverse signaling cascades to promote Yersinia uptake.
  Journal
J Cell Sci 115:2689-700 (2002)
Reference
PMID:11734206
  Authors
McGee K, Zettl M, Way M, Fallman M
  Title
A role for N-WASP in invasin-promoted internalisation.
  Journal
FEBS Lett 509:59-65 (2001)
DOI:10.1016/S0014-5793(01)03139-8
Reference
PMID:15516995
  Authors
Pizarro-Cerda J, Cossart P
  Title
Subversion of phosphoinositide metabolism by intracellular bacterial pathogens.
  Journal
Nat Cell Biol 6:1026-33 (2004)
DOI:10.1038/ncb1104-1026
Reference
PMID:27569559
  Authors
Chung LK, Park YH, Zheng Y, Brodsky IE, Hearing P, Kastner DL, Chae JJ, Bliska JB
  Title
The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome.
  Journal
Cell Host Microbe 20:296-306 (2016)
DOI:10.1016/j.chom.2016.07.018
Reference
PMID:15060067
  Authors
Schotte P, Denecker G, Van Den Broeke A, Vandenabeele P, Cornelis GR, Beyaert R
  Title
Targeting Rac1 by the Yersinia effector protein YopE inhibits caspase-1-mediated maturation and release of interleukin-1beta.
  Journal
J Biol Chem 279:25134-42 (2004)
DOI:10.1074/jbc.M401245200
Reference
PMID:10489373
  Authors
Orth K, Palmer LE, Bao ZQ, Stewart S, Rudolph AE, Bliska JB, Dixon JE
  Title
Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector.
  Journal
Science 285:1920-3 (1999)
DOI:10.1126/science.285.5435.1920
Reference
PMID:16301742
  Authors
Zhou H, Monack DM, Kayagaki N, Wertz I, Yin J, Wolf B, Dixit VM
  Title
Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-kappa B activation.
  Journal
J Exp Med 202:1327-32 (2005)
DOI:10.1084/jem.20051194
Reference
PMID:16339560
  Authors
Haase R, Richter K, Pfaffinger G, Courtois G, Ruckdeschel K
  Title
Yersinia outer protein P suppresses TGF-beta-activated kinase-1 activity to impair innate immune signaling in Yersinia enterocolitica-infected cells.
  Journal
J Immunol 175:8209-17 (2005)
DOI:10.4049/jimmunol.175.12.8209
Reference
PMID:16845370
  Authors
Thiefes A, Wolf A, Doerrie A, Grassl GA, Matsumoto K, Autenrieth I, Bohn E, Sakurai H, Niedenthal R, Resch K, Kracht M
  Title
The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway.
  Journal
EMBO Rep 7:838-44 (2006)
DOI:10.1038/sj.embor.7400754
Reference
PMID:26651944
  Authors
Rosadini CV, Zanoni I, Odendall C, Green ER, Paczosa MK, Philip NH, Brodsky IE, Mecsas J, Kagan JC
  Title
A Single Bacterial Immune Evasion Strategy Dismantles Both MyD88 and TRIF Signaling Pathways Downstream of TLR4.
  Journal
Cell Host Microbe 18:682-93 (2015)
DOI:10.1016/j.chom.2015.11.006
Reference
PMID:24034616
  Authors
Rolan HG, Durand EA, Mecsas J
  Title
Identifying Yersinia YopH-targeted signal transduction pathways that impair neutrophil responses during in vivo murine infection.
  Journal
Cell Host Microbe 14:306-17 (2013)
DOI:10.1016/j.chom.2013.08.013
Reference
PMID:14623872
  Authors
Alonso A, Bottini N, Bruckner S, Rahmouni S, Williams S, Schoenberger SP, Mustelin T
  Title
Lck dephosphorylation at Tyr-394 and inhibition of T cell antigen receptor signaling by Yersinia phosphatase YopH.
  Journal
J Biol Chem 279:4922-8 (2004)
DOI:10.1074/jbc.M308978200
Related
pathway
hsa04510  Focal adhesion
hsa04620  Toll-like receptor signaling pathway
hsa04621  NOD-like receptor signaling pathway
hsa04660  T cell receptor signaling pathway
hsa04666  Fc gamma R-mediated phagocytosis
hsa04810  Regulation of actin cytoskeleton
KO pathway
ko05135   
LinkDB

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