KEGG PATHWAY: hsa04623

PATHWAY: hsa04623

Entry

hsa04623                    Pathway

Name

Cytosolic DNA-sensing pathway - Homo sapiens (human)

Description

Specific families of pattern recognition receptors are responsible for detecting foreign DNA from invading microbes or host cells and generating innate immune responses. DAI is the first identified sensor of cytosolic DNA which activates the IRF and NF-{kappa}B transcription factors, leading to production of type I interferon and other cytokines. The second type of cytoplasmic DNA sensor is AIM2. Upon sensing DNA, AIM2 triggers the assembly of the inflammasome, culminating in interleukin maturation. In addition to these receptors, there is a mechanism to sense foreign DNA, with the host RNA polymerase III converting the DNA into RNA for recognition by the RNA sensor RIG-I. These pathways provide various means to alert the cell.

Class

Organismal Systems; Immune system

Pathway map

hsa04623

Cytosolic DNA-sensing pathway

Network

Element

N00395

cGAS-STING signaling pathway

N01571

DNA degradation by extracellular/endolysosomal DNAse

Drug

D08978

Pralnacasan (USAN/INN)

D10416

Belnacasan (USAN/INN)

D11449

Etokimab (USAN)

D12352

Eclitasertib (USAN/INN)

D12375

Tozorakimab (USAN/INN)

D12720

Nibrozetone (USAN)

D12821

Flizasertib (USAN/INN)

D12846

Ocadusertib (USAN)

Organism

Homo sapiens (human) [GN:hsa]

Gene

11128

POLR3A; RNA polymerase III subunit A [KO:K03018] [EC:2.7.7.6]

55703

POLR3B; RNA polymerase III subunit B [KO:K03021] [EC:2.7.7.6]

10623

POLR3C; RNA polymerase III subunit C [KO:K03023]

661	POLR3D; RNA polymerase III subunit D [KO:K03026]

55718

POLR3E; RNA polymerase III subunit E [KO:K14721]

9533	POLR1C; RNA polymerase I and III subunit C [KO:K03027]

51728

POLR3K; RNA polymerase III subunit K [KO:K03019]

51082

POLR1D; RNA polymerase I and III subunit D [KO:K03020]

171568

POLR3H; RNA polymerase III subunit H [KO:K03022]

84265

POLR3GL; RNA polymerase III subunit GL [KO:K03024]

10622

POLR3G; RNA polymerase III subunit G [KO:K03024]

10621

POLR3F; RNA polymerase III subunit F [KO:K03025]

5434	POLR2E; RNA polymerase II, I and III subunit E [KO:K03013]

5435	POLR2F; RNA polymerase II, I and III subunit F [KO:K03014]

5437	POLR2H; RNA polymerase II, I and III subunit H [KO:K03016]

5440	POLR2K; RNA polymerase II, I and III subunit K [KO:K03009]

5441	POLR2L; RNA polymerase II, I and III subunit L [KO:K03007]

23586

RIGI; RNA sensor RIG-I [KO:K12646] [EC:5.6.2.6]

57506

MAVS; mitochondrial antiviral signaling protein [KO:K12648]

4790	NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]

5970	RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]

3569	IL6; interleukin 6 [KO:K05405]

5093	PCBP1; poly(rC) binding protein 1 [KO:K12889]

10146

G3BP1; G3BP stress granule assembly factor 1 [KO:K17265] [EC:5.6.2.5 5.6.2.3]

85364

ZCCHC3; zinc finger CCHC-type containing 3 [KO:K27162]

115004

CGAS; cyclic GMP-AMP synthase [KO:K17834] [EC:2.7.7.86]

340061

STING1; stimulator of interferon response cGAMP interactor 1 [KO:K12654]

29800

ZDHHC1; zinc finger DHHC-type containing 1 [KO:K20027] [EC:2.3.1.225]

653082

ZDHHC11B; zinc finger DHHC-type containing 11B [KO:K20027] [EC:2.3.1.225]

79844

ZDHHC11; zinc finger DHHC-type containing 11 [KO:K20027] [EC:2.3.1.225]

51428

DDX41; DEAD-box helicase 41 [KO:K13116] [EC:5.6.2.7]

3428	IFI16; interferon gamma inducible protein 16 [KO:K20914]

29110

TBK1; TANK binding kinase 1 [KO:K05410] [EC:2.7.11.10]

9641	IKBKE; inhibitor of nuclear factor kappa B kinase subunit epsilon [KO:K07211] [EC:2.7.11.10]

3661	IRF3; interferon regulatory factor 3 [KO:K05411]

3665	IRF7; interferon regulatory factor 7 [KO:K09447]

3439	IFNA1; interferon alpha 1 [KO:K05414]

3440	IFNA2; interferon alpha 2 [KO:K05414]

3441	IFNA4; interferon alpha 4 [KO:K05414]

3442	IFNA5; interferon alpha 5 [KO:K05414]

3443	IFNA6; interferon alpha 6 [KO:K05414]

3444	IFNA7; interferon alpha 7 [KO:K05414]

3445	IFNA8; interferon alpha 8 [KO:K05414]

3446	IFNA10; interferon alpha 10 [KO:K05414]

3447	IFNA13; interferon alpha 13 [KO:K05414]

3448	IFNA14; interferon alpha 14 [KO:K05414]

3449	IFNA16; interferon alpha 16 [KO:K05414]

3451	IFNA17; interferon alpha 17 [KO:K05414]

3452	IFNA21; interferon alpha 21 [KO:K05414]

3456	IFNB1; interferon beta 1 [KO:K05415]

81030

ZBP1; Z-DNA binding protein 1 [KO:K12965]

8737	RIPK1; receptor interacting serine/threonine kinase 1 [KO:K02861] [EC:2.7.11.1]

11035

RIPK3; receptor interacting serine/threonine kinase 3 [KO:K08847] [EC:2.7.11.1]

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]

4793	NFKBIB; NFKB inhibitor beta [KO:K02581]

4792	NFKBIA; NFKB inhibitor alpha [KO:K04734]

6351	CCL4; C-C motif chemokine ligand 4 [KO:K12964]

9560	CCL4L2; C-C motif chemokine ligand 4 like 2 [KO:K12964]

388372

CCL4L1; C-C motif chemokine ligand 4 like 1 [KO:K12964]

6352	CCL5; C-C motif chemokine ligand 5 [KO:K12499]

3627	CXCL10; C-X-C motif chemokine ligand 10 [KO:K12671]

9447	AIM2; absent in melanoma 2 [KO:K12966]

114548

NLRP3; NLR family pyrin domain containing 3 [KO:K12800]

4210	MEFV; MEFV innate immunity regulator, pyrin [KO:K12803]

8772	FADD; Fas associated via death domain [KO:K02373]

841	CASP8; caspase 8 [KO:K04398] [EC:3.4.22.61]

29108

PYCARD; PYD and CARD domain containing [KO:K12799]

834	CASP1; caspase 1 [KO:K01370] [EC:3.4.22.36]

197259

MLKL; mixed lineage kinase domain like pseudokinase [KO:K08849] [EC:2.7.11.1]

836	CASP3; caspase 3 [KO:K02187] [EC:3.4.22.56]

840	CASP7; caspase 7 [KO:K04397] [EC:3.4.22.60]

1687	GSDME; gasdermin E [KO:K22146]

79792

GSDMD; gasdermin D [KO:K20917]

3553	IL1B; interleukin 1 beta [KO:K04519]

3606	IL18; interleukin 18 [KO:K05482]

90865

IL33; interleukin 33 [KO:K12967]

103	ADAR; adenosine deaminase RNA specific [KO:K12968] [EC:3.5.4.37]

25939

SAMHD1; SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 [KO:K22544] [EC:3.1.5.-]

11277

TREX1; three prime repair exonuclease 1 [KO:K10790] [EC:3.1.11.2]

1777	DNASE2; deoxyribonuclease 2, lysosomal [KO:K01158] [EC:3.1.22.1]

58511

DNASE2B; deoxyribonuclease 2 beta [KO:K01158] [EC:3.1.22.1]

Compound

C00039

DNA

C20640

Cyclic GMP-AMP

Reference

PMID:19362700

Authors

Yanai H, Savitsky D, Tamura T, Taniguchi T

Title

Regulation of the cytosolic DNA-sensing system in innate immunity: a current view.

Journal

Curr Opin Immunol 21:17-22 (2009)
DOI:10.1016/j.coi.2009.01.005

Reference

PMID:19497760

Authors

Vilaysane A, Muruve DA

Title

The innate immune response to DNA.

Journal

Semin Immunol 21:208-14 (2009)
DOI:10.1016/j.smim.2009.05.006

Reference

PMID:18573338

Authors

Takeshita F, Ishii KJ

Title

Intracellular DNA sensors in immunity.

Journal

Curr Opin Immunol 20:383-8 (2008)
DOI:10.1016/j.coi.2008.05.009

Reference

PMID:19122387

Authors

Takaoka A, Shinohara S

Title

DNA sensors in innate immune system.

Journal

Uirusu 58:37-46 (2008)
DOI:10.2222/jsv.58.37

Reference

PMID:18280611

Authors

Takaoka A, Taniguchi T

Title

Cytosolic DNA recognition for triggering innate immune responses.

Journal

Adv Drug Deliv Rev 60:847-57 (2008)
DOI:10.1016/j.addr.2007.12.002

Reference

PMID:18941233

Authors

Kaiser WJ, Upton JW, Mocarski ES

Title

Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors.

Journal

J Immunol 181:6427-34 (2008)
DOI:10.4049/jimmunol.181.9.6427

Reference

PMID:19590578

Authors

Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K, Hofmann K, Vazquez J, Benedict CA, Tschopp J

Title

DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB.

Journal

EMBO Rep 10:916-22 (2009)
DOI:10.1038/embor.2009.109

Reference

PMID:18375758

Authors

Wang Z, Choi MK, Ban T, Yanai H, Negishi H, Lu Y, Tamura T, Takaoka A, Nishikura K, Taniguchi T

Title

Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules.

Journal

Proc Natl Acad Sci U S A 105:5477-82 (2008)
DOI:10.1073/pnas.0801295105

Reference

PMID:18724932

Authors

Stetson DB, Ko JS, Heidmann T, Medzhitov R

Title

Trex1 prevents cell-intrinsic initiation of autoimmunity.

Journal

Cell 134:587-98 (2008)
DOI:10.1016/j.cell.2008.06.032

Reference

PMID:19321146

Authors

Schroder K, Muruve DA, Tschopp J

Title

Innate immunity: cytoplasmic DNA sensing by the AIM2 inflammasome.

Journal

Curr Biol 19:R262-5 (2009)
DOI:10.1016/j.cub.2009.02.011

Reference

PMID:19567913

Authors

Krieg AM

Title

AIMing 2 detect foreign DNA.

Journal

Sci Signal 2:pe39 (2009)
DOI:10.1126/scisignal.277pe39

Reference

PMID:19665965

Authors

O'Neill LA

Title

DNA makes RNA makes innate immunity.

Journal

Cell 138:428-30 (2009)
DOI:10.1016/j.cell.2009.07.021

Reference

PMID:16286919

Authors

Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, Ludwig H, Sutter G, Suzuki K, Hemmi H, Sato S, Yamamoto M, Uematsu S, Kawai T, Takeuchi O, Akira S

Title

A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA.

Journal

Nat Immunol 7:40-8 (2006)
DOI:10.1038/ni1282

Reference

PMID:19767723

Authors

Cao X

Title

New DNA-sensing pathway feeds RIG-I with RNA.

Journal

Nat Immunol 10:1049-51 (2009)
DOI:10.1038/ni1009-1049