KEGG   PATHWAY: lav05135
Entry
lav05135                    Pathway                                
Name
Yersinia infection - Loxodonta africana (African savanna elephant)
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
lav05135  Yersinia infection
lav05135

Organism
Loxodonta africana (African savanna elephant) [GN:lav]
Gene
100667853  FN1; fibronectin isoform X8 [KO:K05717]
100674409  ITGA4; integrin alpha-4 [KO:K06483]
100676951  ITGA5; integrin alpha-5 [KO:K06484]
100664978  ITGB1; integrin beta-1 isoform X1 [KO:K05719]
100676933  RHOG; rho-related GTP-binding protein RhoG [KO:K07863]
100675475  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
100668436  PTK2; LOW QUALITY PROTEIN: focal adhesion kinase 1 [KO:K05725] [EC:2.7.10.2]
100667505  PTK2B; protein-tyrosine kinase 2-beta isoform X1 [KO:K05871] [EC:2.7.10.2]
100659273  CRK; adapter molecule crk isoform X1 [KO:K04438]
100662046  CRKL; crk-like protein [KO:K04438]
100675124  BCAR1; LOW QUALITY PROTEIN: breast cancer anti-estrogen resistance protein 1 [KO:K05726]
100677626  ELMO1; engulfment and cell motility protein 1 isoform X1 [KO:K12366]
100665325  ELMO2; engulfment and cell motility protein 2 isoform X1 [KO:K18985]
100663543  DOCK1; dedicator of cytokinesis protein 1 [KO:K13708]
104847364  uncharacterized protein LOC104847364 [KO:K06856]
104846329  FCGR2A; low affinity immunoglobulin gamma Fc region receptor II-a isoform X2 [KO:K06472]
100664204  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
100670080  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
100674713  PIP5K1A; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha isoform X3 [KO:K00889] [EC:2.7.1.68]
100655311  phosphatidylinositol 4-phosphate 5-kinase type-1 gamma isoform X5 [KO:K00889] [EC:2.7.1.68]
100675521  PIP5K1B; phosphatidylinositol 4-phosphate 5-kinase type-1 beta [KO:K00889] [EC:2.7.1.68]
100653925  ARF6; ADP-ribosylation factor 6 [KO:K07941]
111747983  collagen alpha-1(I) chain-like [KO:K23612]
100661328  WASL; neural Wiskott-Aldrich syndrome protein [KO:K23612]
111751670  basic proline-rich protein-like [KO:K23612]
100668085  ACTR2; actin-related protein 2 [KO:K17260]
100677423  ACTR3; actin-related protein 3 [KO:K18584]
100674901  ACTR3B; actin-related protein 3B [KO:K18584]
100660412  ARPC1B; LOW QUALITY PROTEIN: actin-related protein 2/3 complex subunit 1B [KO:K05757]
100660125  ARPC1A; actin-related protein 2/3 complex subunit 1A [KO:K05757]
100665290  ARPC2; actin-related protein 2/3 complex subunit 2 isoform X2 [KO:K05758]
100654357  ARPC3; actin-related protein 2/3 complex subunit 3 [KO:K05756]
100666528  ARPC5L; actin-related protein 2/3 complex subunit 5-like protein [KO:K05754]
100670140  ARPC5; actin-related protein 2/3 complex subunit 5 [KO:K05754]
100670743  ACTG1; actin, cytoplasmic 2 [KO:K05692]
100654618  ACTB; actin, cytoplasmic 1 [KO:K05692]
100658830  WIPF1; WAS/WASL-interacting protein family member 1 isoform X1 [KO:K19475]
100666191  WIPF2; WAS/WASL-interacting protein family member 2 [KO:K19475]
111749750  WIPF3; LOW QUALITY PROTEIN: WAS/WASL-interacting protein family member 3 [KO:K19475]
100657467  BAIAP2; LOW QUALITY PROTEIN: brain-specific angiogenesis inhibitor 1-associated protein 2 [KO:K05627]
100675212  WASF2; wiskott-Aldrich syndrome protein family member 2 [KO:K05748]
100671127  PXN; paxillin isoform X5 [KO:K05760]
100654541  GIT2; ARF GTPase-activating protein GIT2 isoform X1 [KO:K12487]
100655656  ARHGEF7; rho guanine nucleotide exchange factor 7 isoform X4 [KO:K13710]
100664103  CDC42; cell division control protein 42 homolog [KO:K04393]
100677772  WAS; LOW QUALITY PROTEIN: wiskott-Aldrich syndrome protein [KO:K05747]
100656672  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
100661002  ARHGEF12; rho guanine nucleotide exchange factor 12 isoform X1 [KO:K07532]
100674589  ARHGEF1; rho guanine nucleotide exchange factor 1 isoform X2 [KO:K12330]
100661138  ARHGEF28; rho guanine nucleotide exchange factor 28 [KO:K21072]
100677447  RHOA; transforming protein RhoA [KO:K04513]
100657418  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
100658857  ROCK2; rho-associated protein kinase 2 isoform X1 [KO:K17388] [EC:2.7.11.1]
100667296  FYB1; FYN-binding protein 1 isoform X3 [KO:K17698]
100655428  SKAP2; src kinase-associated phosphoprotein 2 [KO:K23471]
100669613  NLRP3; NACHT, LRR and PYD domains-containing protein 3 isoform X1 [KO:K12800]
100675485  PKN1; LOW QUALITY PROTEIN: serine/threonine-protein kinase N1 [KO:K06071] [EC:2.7.11.13]
100664466  PKN2; serine/threonine-protein kinase N2 isoform X1 [KO:K23691] [EC:2.7.11.13]
100654322  RPS6KA6; ribosomal protein S6 kinase alpha-6 isoform X1 [KO:K04373] [EC:2.7.11.1]
100658801  RPS6KA2; ribosomal protein S6 kinase alpha-2 isoform X1 [KO:K04373] [EC:2.7.11.1]
100659843  RPS6KA3; ribosomal protein S6 kinase alpha-3 [KO:K04373] [EC:2.7.11.1]
100676062  RPS6KA1; LOW QUALITY PROTEIN: ribosomal protein S6 kinase alpha-1 [KO:K04373] [EC:2.7.11.1]
100673509  MEFV; LOW QUALITY PROTEIN: pyrin [KO:K12803]
100675310  LIMK1; LOW QUALITY PROTEIN: LIM domain kinase 1 [KO:K05743] [EC:2.7.11.1]
100664299  PYCARD; apoptosis-associated speck-like protein containing a CARD [KO:K12799]
100668369  IL18; interleukin-18 isoform X1 [KO:K05482]
100674746  IL1B; interleukin-1 beta [KO:K04519]
100654493  TLR4; toll-like receptor 4 [KO:K10160]
100659447  MYD88; myeloid differentiation primary response protein MyD88 [KO:K04729]
100653528  IRAK4; interleukin-1 receptor-associated kinase 4 [KO:K04733] [EC:2.7.11.1]
100676181  IRAK1; LOW QUALITY PROTEIN: interleukin-1 receptor-associated kinase 1 [KO:K04730] [EC:2.7.11.1]
100671471  TRAF6; TNF receptor-associated factor 6 [KO:K03175] [EC:2.3.2.27]
100670400  TRAF2; TNF receptor-associated factor 2 isoform X2 [KO:K03173] [EC:2.3.2.27]
100660911  TAB1; LOW QUALITY PROTEIN: TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 [KO:K04403]
100656450  TAB2; TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 isoform X2 [KO:K04404]
100667170  MAP3K7; mitogen-activated protein kinase kinase kinase 7 isoform X2 [KO:K04427] [EC:2.7.11.25]
100661492  IKBKG; LOW QUALITY PROTEIN: NF-kappa-B essential modulator [KO:K07210]
100664361  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
100657363  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X3 [KO:K07209] [EC:2.7.11.10]
100675651  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
100662194  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100654730  RELA; transcription factor p65 isoform X2 [KO:K04735]
100667623  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100657587  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100658240  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100665157  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100675607  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 isoform X1 [KO:K04432] [EC:2.7.12.2]
100662511  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
100673331  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100656926  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100661039  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
100655007  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
100673238  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
100654943  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100674229  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100673395  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100674799  FOS; LOW QUALITY PROTEIN: proto-oncogene c-Fos [KO:K04379]
100670432  JUN; transcription factor AP-1 [KO:K04448]
100654083  TICAM1; TIR domain-containing adapter molecule 1 [KO:K05842]
100661026  TBK1; serine/threonine-protein kinase TBK1 [KO:K05410] [EC:2.7.11.10]
100667571  IRF3; interferon regulatory factor 3 [KO:K05411]
100677125  TNF; tumor necrosis factor isoform X2 [KO:K03156]
100660846  IL6; interleukin-6 [KO:K05405]
100664099  CXCL8; interleukin-8 [KO:K10030]
100666438  IFNB1; interferon beta [KO:K05415]
100657948  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100658340  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100666266  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100653731  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100665045  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100675496  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100663184  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100657536  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100660187  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100675105  GSK3B; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
100675489  C-C motif chemokine 2-like [KO:K14624]
100675007  CD4; LOW QUALITY PROTEIN: T-cell surface glycoprotein CD4 [KO:K06454]
100654262  CD8A; T-cell surface glycoprotein CD8 alpha chain isoform X2 [KO:K06458]
100666557  LCK; tyrosine-protein kinase Lck isoform X2 [KO:K05856] [EC:2.7.10.2]
100676739  uncharacterized protein LOC100676739 [KO:K10785]
111749403  immunoglobulin gamma-1 heavy chain-like [KO:K10785]
100666693  tyrosine-protein kinase ZAP-70 [KO:K07360] [EC:2.7.10.2]
100675602  LAT; linker for activation of T-cells family member 1 [KO:K07362]
100662993  LCP2; lymphocyte cytosolic protein 2 isoform X1 [KO:K07361]
100662747  VAV3; guanine nucleotide exchange factor VAV3 isoform X2 [KO:K05730]
100673242  VAV1; LOW QUALITY PROTEIN: proto-oncogene vav [KO:K05730]
100677422  VAV2; guanine nucleotide exchange factor VAV2 [KO:K05730]
100677739  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
100655623  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X3 [KO:K04446]
100672662  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
100658037  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X2 [KO:K17333]
100656398  IL2; interleukin-2 [KO:K05429]
100665398  IL10; interleukin-10 isoform X2 [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
lav04510  Focal adhesion
lav04620  Toll-like receptor signaling pathway
lav04621  NOD-like receptor signaling pathway
lav04660  T cell receptor signaling pathway
lav04666  Fc gamma R-mediated phagocytosis
lav04810  Regulation of actin cytoskeleton
KO pathway
ko05135   
LinkDB

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