The essential adaptors of innate immune signaling

Huihui Chen, Zhengfan Jiang()

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Protein Cell ›› 2013, Vol. 4 ›› Issue (1) : 27-39. DOI: 10.1007/s13238-012-2063-0
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The essential adaptors of innate immune signaling

  • Huihui Chen, Zhengfan Jiang()
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Abstract

Microbial components and the endogenous molecules released from damaged cells can stimulate germline- encoded pattern recognition receptors (PRRs) to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/ MAVS/STING/Caspase-1, where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/ AP-1 and the signal transducer and activator of transcription 6 (STAT6) to trigger the expression of type I interferons and inflammatory cytokines or the assembly of inflammasomes. Most pleiotropic cytokines are secreted and bind to specific receptors, activating the signaling pathways including JAK-STAT for the proliferation, differentiation and functional capacity of immune cells. This review focuses on several critical adaptors in innate immune signaling cascades and recent progress in their molecular mechanisms.

Keywords

innate immunity / adaptor / STING / STAT6

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Huihui Chen, Zhengfan Jiang. The essential adaptors of innate immune signaling. Prot Cell, 2013, 4(1): 27‒39 https://doi.org/10.1007/s13238-012-2063-0

References

[1] Arimoto, K.I., Takahashi, H., Hishiki, T., Konishi, H., Fujita, T., and Shimotohno, K. (2007). Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc Natl Acad Sci U S A 104, 7500-7505 .10.1073/pnas.0611551104
[2] Barber, G.N. (2011). Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses. Curr Opin Immunol 23, 10-20 .10.1016/j.coi.2010.12.015
[3] Bhattacharya, B., Carlsten, J., Sabo, E., Kethu, S., Meitner, P., Tavares, R., Jakate, S., Mangray, S., Aswad, B., and Resnick, M.B. (2007). Increased expression of eotaxin-3 distinguishes between eosinophilic esophagitis and gastroesophageal reflux disease. Hum Pathol 38, 1744-1753 .10.1016/j.humpath.2007.05.008
[4] Brierley, M.M., and Fish, E.N. (2005). Stats: multifaceted regulators of transcription. J Interf Cytok Res 25, 733-744 .10.1089/jir.2005.25.733
[5] Brown, J., Wang, H., Hajishengallis, G.N., and Martin, M. (2011). TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J Dent Res 90, 417-427 .10.1177/0022034510381264
[6] Bürckstümmer, T., Baumann, C., Blüml, S., Dixit, E., Dürnberger, G., Jahn, H., Planyavsky, M., Bilban, M., Colinge, J., Bennett, K. L., . (2009). An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol 10, 266-272 .10.1038/ni.1702
[7] Cao, Z.D., Henzel, W.J., and Gao, X. (1996). IRAK: a kinase associated with the interleukin-1 receptor. Science 271, 1128-1131 .10.1126/science.271.5252.1128
[8] Chapoval, S., Dasgupta, P., Dorsey, N.J., and Keegan, A.D. (2010). Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6. J Leuk Biol 87, 1011-1018 .10.1189/jlb.1209772
[9] Chen, H.H., Sun, H., You, F.P., Sun, W.X., Zhou, X., Chen, L., Yang, J., Wang, Y.T., Tang, H., Guan, Y.K., . (2011). Activation of STAT6 by STING is critical for antiviral innate immunity. Cell 147, 436-446 .10.1016/j.cell.2011.09.022
[10] Chen, Z.J. (2005). Ubiquitin signalling in the NF-κB pathway. Nat Cell Biol 7, 758-765 .10.1038/ncb0805-758
[11] Chevrier, N., Mertins, P., Artyomov, M.N., Shalek, A.K., Iannacone, M., Ciaccio, M.F., Gat-Viks, I., Tonti, E., DeGrace, M.M., Clauser, K.R., . (2011). Systematic discovery of TLR signaling components delineates viral-sensing circuits. Cell 147, 853-867 .10.1016/j.cell.2011.10.022
[12] Dixit, E., Boulant, S., Zhang, Y.J., Lee, A.S.Y., Odendall, C., Shum, B., Hacohen, N., Chen, Z.J., Whelan, S.P., Fransen, M., . (2010). Peroxisomes are signaling platforms for antiviral innate immunity. Cell 141, 668-681 .10.1016/j.cell.2010.04.018
[13] Fernandes-Alnemri, T., Yu, J.-W., Datta, P., Wu, J.H., and Alnemri, E.S. (2009). AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509-513.10.1038/nature07710
[14] H?cker, H., Redecke, V., Blagoev, B., Kratchmarova, I., Hsu, L.-C., Wang, G.G., Kamps, M.P., Raz, E., Wagner, H., H?cker, G.,. (2006). Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439, 204-207 .10.1038/nature04369
[15] Hebenstreit, D., Wirnsberger, G., Horejs-Hoeck, J., and Duschl, A. (2006). Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine Growth Factor Rev 17, 173-188 .10.1016/j.cytogfr.2006.01.004
[16] Hoeck, J., and Woisetschl?ger, M. (2001). STAT6 mediates eotaxin- 1 expression in IL-4 or TNF-alpha-induced fibroblasts. J Immunol 166, 4507-4515 .
[17] Horng, T., Barton, G.M., and Medzhitov, R. (2001). TIRAP: an adaptor molecule in the Toll signaling pathway. Nat Immunol 2, 835-841 .10.1038/ni0901-835
[18] Hornung, V., Ablasser, A., Charrel-Dennis, M., Bauernfeind, F., Horvath, G., Caffrey, D.R., Latz, E., and Fitzgerald, K.A. (2009). AIM2 recognizes cytosolic dsDNA and forms a caspase- 1-activating inflammasome with ASC. Nature 458, 514-518 .10.1038/nature07725
[19] Hornung, V., Ellegast, J., Kim, S., Brzózka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K.-K., Schlee, M., . (2006). 5’-Triphosphate RNA is the ligand for RIG-I. Science 314, 994-997 .10.1126/science.1132505
[20] Hou, F.J., Sun, L.J., Zheng, H., Skaug, B., Jiang, Q.X., and Chen, Z.J. (2011). MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146, 448-461 .10.1016/j.cell.2011.06.041
[21] Hundley, T.R., Gilfillan, A.M., Tkaczyk, C., Andrade, M.V., Metcalfe, D.D., Beaven, M.A. (2004). Kit and FcepsilonRI mediate unique and convergent signals for release of inflammatory mediators from human mast cells. Blood 104, 2410-2417 .10.1182/blood-2004-02-0631
[22] Ishikawa, H., Ma, Z., and Barber, G.N. (2009). STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788-792 .10.1038/nature08476
[23] Jiang, X.M., Kinch, L.N., Brautigam, C.A., Chen, X., Du, F.H., Grishin, N.V., and Chen, Z.J. (2012). Ubiquitin-induced oligomerization of the RNA sensors RIG-I and Mda5 activates antiviral innate immune response. Immunity 36, 959-973 .10.1016/j.immuni.2012.03.022
[24] Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K.J., . (2006). Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101-105 .10.1038/nature04734
[25] Kawai, T., Adachi, O., Ogawa, T., Takeda, K., and Akira, S. (1999). Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115-122 .10.1016/S1074-7613(00)80086-2
[26] Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K.J., Takeuchi, O., and Akira, S. (2005). IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6, 981-988 .10.1038/ni1243
[27] Kofoed, E.M., and Vance, R.E. (2011). Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477, 592-595 .10.1038/nature10394
[28] Kumar, H., Kawai, T., and Akira, S. (2011). Pathogen recognition by the innate immune system. Intl Rev Immunol 30, 16-34 .10.3109/08830185.2010.529976
[29] Lee, M.S., and Kim, Y.J. (2007). Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu Rev Biochem 76, 447-480 .10.1146/annurev.biochem.76.060605.122847
[30] Mahad, D.J., and Ransohoff, R.M. (2003). The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Semin Immunol 15, 23-32 .10.1016/S1044-5323(02)00125-2
[31] Marta, M., Jian, N., Ping, F., and Vishva, M.D. (1997). IRAK (Pelle) Family Member IRAK-2 AND MyD88 as Proximal Mediators of IL-1 Signaling. Science 278, 1612-1615 .10.1126/science.278.5343.1612
[32] Meylan, E., Curran, J., Hofmann, K., Moradpour, D., Binder, M., Bartenschlager, R., and Tschopp, J. (2005). Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167-1172 .10.1038/nature04193
[33] Moore, C.B., Bergstralh, D.T., Duncan, J.A., Lei, Y., Morrison, T.E., Zimmermann, A.G., Accavitti-Loper, M.A., Madden, V.J., Sun, L.J., Ye, Z.M., . (2008). NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451, 573-577 .10.1038/nature06501
[34] Nakayama, T., Watanabe, Y., Oiso, N., Higuchi, T., Shigeta, A., Mizuguchi, N., Katou, F., Hashimoto, K., Kawada, A., and Yoshie, O. (2010). Eotaxin-3/CC chemokine ligand 26 is a functional ligand for CX3CR1. J Immunol 185, 6472-6479 .10.4049/jimmunol.0904126
[35] Nishimura, M., and Naito, S. (2005). Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Biol Pharm Bull 28, 886-892 .10.1248/bpb.28.886
[36] Okabe, Y., Sano, T., and Nagata, S. (2009). Regulation of the innate immune response by threonine-phosphatase of Eyes absent. Nature 460, 520-524 .
[37] Pétrilli, V., Papin, S., Dostert, C., Mayor, A., Martinon, F., and Tschopp, J. (2007). Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 14, 1583-1589 .10.1038/sj.cdd.4402195
[38] Rothenfusser, S., Goutagny, N., Diperna, G., Monks, B.G., Schoenemeyer, A., Akira, S., Fitzgerald, K.A., Gong, M., and Yamamoto, M. (2005). The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid- inducible gene-I. J Immunol 175, 5260-5268 .
[39] Saito, T., Hirai, R., Loo, Y.-M., Owen, D., Johnson, C.L., Sinha, S.C., Akira, S., Fujita, T., and Gale, M., Jr. (2007). Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc Natl Acad Sci U S A 104, 582-587 .10.1073/pnas.0606699104
[40] Satoh, T., Kato, H., Kumagai, Y., Yoneyama, M., Sato, S., Matsushita, K., Tsujimura, T., Fujita, T., Akira, S., and Takeuchi, O. (2010). LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc Natl Acad Sci U S A 107, 1512-1517 .10.1073/pnas.0912986107
[41] Schroder, K., and Tschopp, J. (2010). The inflammasomes. Cell 140, 821-832 .10.1016/j.cell.2010.01.040
[42] Sehra, S., Bruns, H.A., Ahyi, A.-N.N., Nguyen, E.T., Schmidt, N.W., Michels, E.G., von Bülow, G.-U., and Kaplan, M.H. (2008). IL-4 is a critical determinant in the generation of allergic inflammation initiated by a constitutively active Stat6. J Immunol 180, 3551-3559 .
[43] Sehra, S., Yao, Y.X., Howell, M.D., Nguyen, E.T., Kansas, G.S., Leung, D.Y.M., Travers, J.B., and Kaplan, M.H. (2010). IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation. J Immunol 184, 3186-3190 .10.4049/jimmunol.0901860
[44] Seth, R.B., Sun, L., Ea, C.-K., and Chen, Z.J. (2005). Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3. Cell 122, 669-682 .10.1016/j.cell.2005.08.012
[45] Sun, L., Xing, Y.L., Chen, X.J., Zheng, Y., Yang, Y.D., Nichols, D.B., Clementz, M.A., Banach, B.S., Li, K., Baker, S.C., . (2012). Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. PLoS ONE 7, e30802.10.1371/journal.pone.0030802
[46] Sun, W.X., Li, Y., Chen, L., Chen, H.H., You, F.P., Zhou, X., Zhou, Y., Zhai, Z.H., Chen, D.Y., and Jiang, Z.F. (2009). ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Natl Acad Sci U S A 106, 8653-8658 .10.1073/pnas.0900850106
[47] Tanaka, Y., and Chen. Z.J. (2012). STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci Signal 5, ra20.10.1126/scisignal.2002521
[48] Takeuchi, O., and Akira, S. (2010). Pattern recognition receptors and inflammation. Cell 140, 805-820 .10.1016/j.cell.2010.01.022
[49] Thompson, A.J.V., and Locarnini, S.A. (2007). Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response. Immunol Cell Biol 85, 435-445 .10.1038/sj.icb.7100100
[50] Tseng, P.-H., Matsuzawa, A., Zhang, W.Z., Mino, T., Vignali, D.A.A., and Karin, M. (2010). Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol 11, 70-75 .10.1038/ni.1819
[51] Vogel, S.N., Fitzgerald, K.A., and Fenton, M.J. (2003). TLRs: differential adapter utilization by toll-like receptors mediates TLR-specific patterns of gene expression. Mol Interv 3, 466-477 .10.1124/mi.3.8.466
[52] Wang, C., Deng, L., Hong, M., Akkaraju, G.R., Inoue, J.I., and Chen, Z.J. (2001). TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346-351 .10.1038/35085597
[53] Watters, T.M., Kenny, E.F., and O’Neill, L.A.J. (2007). Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. Immunol Cell Biol 85, 411-419 .10.1038/sj.icb.7100095
[54] Weckmann, M., Collison, A., Simpson, J.L., Kopp, M.V., Wark, P.A.B., Smyth, M.J., Yagita, H., Matthaei, K.I., Hansbro, N., Whitehead, B., . (2007). Critical link between TRAIL and CCL20 for the activation of TH2 cells and the expression of allergic airway disease. Nat Med 13, 1308-1315 .10.1038/nm1660
[55] Weighardt, H., Mages, J., Jusek, G., Kaiser-Moore, S., Lang, R., and Holzmann, B. (2006). Organ-secific role of MyD88 for gene regulation during polymicrobial peritonitis. Infect Immun 74, 3618-3632 .10.1128/IAI.01681-05
[56] Winter, C., Taut, K., Srivastava, M., L?nger, F., Mack, M., Briles, D.E., Paton, J.C., Maus, R., Welte, T., Gunn, M.D., . (2007). Lung-specific overexpression of CC chemokine ligand (CCL) 2 enhances the host defense to Streptococcus pneumoniae infection in mice: role of the CCL2-CCR2 axis. J Immunol 178, 5828-5838 .
[57] Xu, L.-G., Wang, Y.-Y., Han, K.-J., Li, L.-Y., Zhai, Z.H., and Shu, H.-B. (2005). VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol Cell 19, 727-740 .10.1016/j.molcel.2005.08.014
[58] Yamamoto, M., Sato, S., Hemmi, H., Hoshino, K., Kaisho, T., Sanjo, H., Takeuchi, O., Sugiyama, M., Okabe, M., Takeda, K., . (2003). Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640-643 .10.1126/science.1087262
[59] Yan, N., Regalado-Magdos, A.D., Stiggelbout, B., Lee-kirsch, M.A., and Lieberman, J. (2011). The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol 11, 1005-1013 .10.1038/ni.1941
[60] Yoneyama, M., and Fujita, T. (2008). Structural mechanism of RNA recognition by the RIG-I-like receptors. Immunity 29, 178-181 .10.1016/j.immuni.2008.07.009
[61] Zeng, W.W., Sun, L.J., Jiang, X.M., Chen, X., Hou, F.J., Adhikari, A., Xu, M., and Chen, Z.J. (2010). Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 141, 315-330 .10.1016/j.cell.2010.03.029
[62] Zhao, Y., Yang, J.L., Shi, J.J., Gong, Y.-N., Lu, Q.H., Xu, H., Liu, L.P., and Shao, F. (2011). The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596-600 .10.1038/nature10510
[63] Zhong, B., Yang, Y., Li, S., Wang, Y.-Y., Li, Y., Diao, F.C., Lei, C.Q., He, X., Zhang, L., Tien, P., . (2008). The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538-550.10.1016/j.immuni.2008.09.003
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