cGAS的研究进展
Advances of cGAS
DOI: 10.12677/AMS.2017.42009, PDF, HTML, XML, 下载: 2,719  浏览: 9,803  科研立项经费支持
作者: 辛佳静, 郭晓敏, 孟 丽, 汲广东:中国海洋大学海洋生命学院,海洋生物多样性与进化研究所,山东 青岛
关键词: cGASDNA感受器STING免疫进化cGAS DNA Sensor STING Immune Evolution
摘要: 环鸟苷酸-腺苷酸合成酶(cyclic GMP-AMP synthase, cGAS)是一种核酸转移酶,在哺乳动物中具有DNA 感受器的功能,能识别胞质DNA并产生cGAMP (cyclic GMP-AMP),激活干扰素刺激蛋白(stimulator of interferon genes, STING),调控下游的I型干扰素(interferon, IFN)和其他细胞因子的分泌,启动机体的免疫反应。cGAS不仅能够抗病毒,也能抵抗细菌的感染。结构上,cGAS由氨基端的DNA结合位点,中间的催化结构域以及羧基端保守的Mab-21 (male abnormal 21)结构域组成,属于MAB21家族蛋白。进化分析发现,脊椎动物的cGAS来源于祖先Mab-21结构域,并且在鱼类和某些哺乳动物中通过基因组复制产生了cGAS和cGASL基因。本文就cGAS结构和免疫功能的研究进展以及演化情况进行了综述。
Abstract: cGAS (cyclic GMP-AMP synthase), a kind of nucleic acid transferase and one of the latest DNA sensors being found in mammals, could identify DNA in cytoplasm and produce cGAMP (cyclic GMP-AMP) to activate interferon stimulated gene (STING), then activate the type I interferon and other cytokines to execute immune function. It was found that cGAS could not only be involved in antiviral response, but also in antibacteria response. cGAS is composed of DNA binding site in N-terminal, a central catalytic domain and a conserved Mab-21 (male abnormal 21) domain in C-terminus, which belongs to MAB21 family protein. Phylogenetic analysis showed that vertebrate cGAS is derived from ancestral Mab-21 domain, which also produced cGAS-like gene through genome duplication in fishes and some mammals. In this review, we discussed the recent research progress regarding the role of cGAS in immune response and its evolution scenario.
文章引用:辛佳静, 郭晓敏, 孟丽, 汲广东. cGAS的研究进展[J]. 海洋科学前沿, 2017, 4(2): 61-67. https://doi.org/10.12677/AMS.2017.42009

参考文献

[1] Ishii, K.J., Coban, C., Kato, H., Takahashi, K., Torii, Y., Takeshita, F., et al. (2006) A Toll-Like Receptor-Inde- pendent Antiviral Response Induced by Double-Stranded B-Form DNA. Nature Immunology, 7, 40-48.
https://doi.org/10.1038/ni1282
[2] Stetson, D.B., Ko, J.S., Heidmann, T. and Medzhitov, R. (2008) Trex1 Prevents Cell-Intrinsic Initiation of Autoimmunity. Cell, 134, 587-598.
https://doi.org/10.1016/j.cell.2008.06.032
[3] Keating, S.E., Baran, M. and Bowie, A.G. (2011) Cytosolic DNA Sensors Regulating Type I Interferon Induction. Trends in Immunology, 32, 574-581.
https://doi.org/10.1016/j.it.2011.08.004
[4] O’Neill, L.A. (2013) Immunology. Sensing the Dark Side of DNA. Science, 339, 763-764.
https://doi.org/10.1126/science.1234724
[5] Leadbetter, E.A., Rifkin, I.R., Hohlbaum, A.M., Beaudette, B.C., Shlomchik, M.J. and Marshak-Rothstein, A. (2002) Chromatin-IgG Complexes Activate B Cells by Dual Engage-ment of IgM and Toll-Like Receptors. Nature, 416, 603-607.
https://doi.org/10.1038/416603a
[6] Chow, K.L., Hall, D.H. and Emmons, S.W. (1995) The Mab-21 Gene of Caenorhabditis Elegans Encodes a Novel Protein Required for Choice of Alternate Cell Fates. Development, 121, 3615-3626.
[7] Schoggins, J.W., Wilson, S.J., Panis, M., Murphy, M.Y., Jones, C.T., Bieniasz, P., et al. (2011) A Diverse Range of Gene Products Are Effectors of the Type I Interferon Antiviral Response. Nature, 472, 481-485.
https://doi.org/10.1038/nature09907
[8] Wu, J., Sun, L., Chen, X., Du, F., Shi, H., Chen, C., et al. (2013) Cyclic GMP-AMP is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA. Science, 339, 826-830.
https://doi.org/10.1126/science.1229963
[9] Sun, L., Wu, J., Du, F., Chen, X. and Chen, Z.J. (2013) Cyclic GMP-AMP Synthase is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway. Science, 339, 786-791.
https://doi.org/10.1126/science.1232458
[10] 郭晓强, 田占涛, 李娜, 王越甲, 段相林. cGAMP: 一种新的哺乳动物第二信使. 生物化学与生物物理进展, 2013, 40(6).
[11] Cavlar, T., Deimling, T., Ablasser, A., Hopfner, K.P. and Hornung, V. (2013) Species-Specific Detection of the Antiviral Small-Molecule Compound CMA by STING. The EMBO Journal, 32, 1440-1450.
https://doi.org/10.1038/emboj.2013.86
[12] Gao, P., Ascano, M., Wu, Y., Barchet, W., Gaffney, B.L., Zillinger, T., et al. (2013) Cyclic [G(2',5')pA(3',5')p] Is the Metazoan Second Messenger Produced by DNA-Activated Cyclic GMP-AMP Synthase. Cell, 153, 1094-1107.
https://doi.org/10.1016/j.cell.2013.04.046
[13] Civril, F., Deimling, T., Mann, C.C.O., Ablasser, A., Moldt, M., Witte, G., et al. (2013) Structural Mechanism of Cytosolic DNA Sensing by CGAS. Nature, 498, 332-337.
https://doi.org/10.1038/nature12305
[14] Kranzusch, P.J., Lee, A.S., Berger, J.M. and Doudna, J.A. (2013) Structure of Human CGAS Reveals a Conserved Family of Second-Messenger Enzymes in Innate Immunity. Cell Reports, 3, 1362-1368.
https://doi.org/10.1016/j.celrep.2013.05.008
[15] Mann, C.C.O., Kiefersauer, R., Witte, G. and Hopfner, K.P. (2016) Structural and Biochemical Characterization of the Cell Fate Determining Nucleotidyltransferase Fold Protein MAB21L1. Scientific Reports, 6, 27498.
https://doi.org/10.1038/srep27498
[16] Ishikawa, H. and Barber, G.N. (2011) The STING Pathway and Regulation of Innate Immune Signaling in Response to DNA Pathogens. Cellular and Molecular Life Sciences: CMLS, 68, 1157-1165.
[17] Sun, W., Li, Y., Chen, L., Chen, H., You, F., Zhou, X., et al. (2009) ERIS, an Endoplasmic Reticulum IFN Stimulator, Activates Innate Immune Signaling through Dimerization. Proceedings of the National Academy of Sciences of the United States of America, 106, 8653-8658.
https://doi.org/10.1073/pnas.0900850106
[18] Ishikawa, H., Ma, Z. and Barber, G.N. (2009) STING Regulates Intracellular DNA-Mediated, Type I Interferon-Dependent Innate Immunity. Nature, 461, 788-792.
https://doi.org/10.1038/nature08476
[19] Barber, G.N. (2011) Innate Immune DNA Sensing Pathways: STING, AIMII and the Regulation of Interferon Production and Inflammatory Responses. Current Opinion in Immunology, 23, 10-20.
https://doi.org/10.1016/j.coi.2010.12.015
[20] Ablasser, A., Goldeck, M., Cavlar, T., Deimling, T., Witte, G., Rohl, I., et al. (2013) CGAS Produces a 2'-5'-Linked Cyclic Dinucleotide Second Messenger that Activates STING. Nature, 498, 380-384.
https://doi.org/10.1038/nature12306
[21] Li, X., Shu, C., Yi, G., Chaton, C.T., Shelton, C.L., Diao, J., et al. (2013) Cyclic GMP-AMP Synthase Is Activated by Double-Stranded DNA-Induced Oligomerization. Immunity, 39, 1019-1031.
https://doi.org/10.1016/j.immuni.2013.10.019
[22] Tanaka, Y. and Chen, Z.J. (2012) STING Specifies IRF3 Phosphorylation by TBK1 in the Cytosolic DNA Signaling Pathway. Science Signaling, 5, ra20.
https://doi.org/10.1126/scisignal.2002521
[23] Schoggins, J.W., MacDuff, D.A., Imanaka, N., Gainey, M.D., Shrestha, B., Eitson, J.L., et al. (2014) Pan-Viral Specificity of IFN-Induced Genes Reveals New Roles for CGAS in Innate Immunity. Nature, 505, 691-695.
https://doi.org/10.1038/nature12862
[24] Lam, E., Stein, S. and Falck-Pedersen, E. (2014) Adenovirus Detection by the CGAS/STING/TBK1 DNA Sensing Cascade. Journal of Virology, 88, 974-981.
https://doi.org/10.1128/JVI.02702-13
[25] Gao, D., Wu, J., Wu, Y.T., Du, F., Aroh, C., Yan, N., et al. (2013) Cyclic GMP-AMP Synthase is an Innate Immune Sensor of HIV and Other Retroviruses. Science, 341, 903-906.
https://doi.org/10.1126/science.1240933
[26] Storek, K.M., Gertsvolf, N.A., Ohlson, M.B. and Monack, D.M. (2015) CGAS and Ifi204 Cooperate to Produce Type I IFNs in Response to Francisella Infection. Journal of Immunology, 194, 3236-3245.
https://doi.org/10.4049/jimmunol.1402764
[27] Wiens, K.E. and Ernst, J.D. (2016) The Mechanism for Type I Interferon Induction by Mycobacterium Tuberculosis is Bacterial Strain-Dependent. Plos Pathogens, 12, e1005809.
https://doi.org/10.1371/journal.ppat.1005809
[28] Zhang, Y., Yeruva, L., Marinov, A., Prantner, D., Wyrick, P.B., Lupashin, V., et al. (2014) The DNA Sensor, Cyclic GMP-AMP Synthase, is Essential for Induction of IFN-Beta during Chlamydia Trachomatis Infection. Journal of Immunology, 193, 2394-2404.
https://doi.org/10.4049/jimmunol.1302718
[29] Collins, A.C., Cai, H., Li, T., Franco, L.H., Li, X.D., Nair, V.R., et al. (2015) Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium Tuberculosis. Cell Host & Microbe, 17, 820-828.
https://doi.org/10.1016/j.chom.2015.05.005
[30] Dey, B., Dey, R.J., Cheung, L.S., Pokkali, S., Guo, H., Lee, J.H., et al. (2015) A Bacterial Cyclic Dinucleotide Activates the Cytosolic Surveillance Pathway and Mediates Innate Resistance to Tuberculosis. Nature Medicine, 21, 401-406.
https://doi.org/10.1038/nm.3813
[31] Wassermann, R., Gulen, M.F., Sala, C., Perin, S.G., Lou, Y., Rybniker, J., et al. (2015) Mycobacterium Tuberculosis Differentially Activates CGAS- and Inflammasome-Dependent Intracellular Immune Responses through ESX-1. Cell Host & Microbe, 17, 799-810.
https://doi.org/10.1016/j.chom.2015.05.003
[32] Watson, R.O., Bell, S.L., MacDuff, D.A., Kimmey, J.M., Diner, E.J., Olivas, J., et al. (2015) The Cytosolic Sensor CGAS Detects Mycobacterium Tuberculosis DNA to Induce Type I Interferons and Activate Autophagy. Cell Host & Microbe, 17, 811-819.
https://doi.org/10.1016/j.chom.2015.05.004
[33] Andrade, W.A., Agarwal, S., Mo, S., Shaffer, S.A., Dillard, J.P., Schmidt, T., et al. (2016) Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-Like Receptor 4. Cell Reports, 15, 2438-2448.
https://doi.org/10.1016/j.celrep.2016.05.030
[34] Kuchta, K., Knizewski, L., Wyrwicz, L.S., Rychlewski, L. and Ginalski, K. (2009) Comprehensive Classification of Nucleotidyltransferase Fold Proteins: Identification of Novel Families and Their Representatives in Human. Nucleic Acids Research, 37, 7701-7714.
https://doi.org/10.1093/nar/gkp854
[35] Mariani, M., Corradi, A., Baldessari, D., Malgaretti, N., Pozzoli, O., Fesce, R., et al. (1998) Mab21, the Mouse Homolog of a C. Elegans Cell-Fate Specification Gene, Participates in Cerebellar, Midbrain and Eye Development. Mechanisms of Development, 79, 131-135.
https://doi.org/10.1016/S0925-4773(98)00180-4
[36] Wong, Y.M. and Chow, K.L. (2002) Expression of Zebrafish Mab21 Genes Marks the Differentiating Eye, Midbrain and Neural Tube. Mechanisms of Development, 113, 149-152.
https://doi.org/10.1016/S0925-4773(02)00012-6
[37] Cederlund, M.L., Vendrell, V., Morrissey, M.E., Yin, J., Gaora, P.O., Smyth, V.A., et al. (2011) Mab21l2 Transgenics Reveal Novel Expression Patterns of Mab21l1 and Mab21l2, and Conserved Promoter Regulation without Sequence Conservation. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 240, 745-754.
https://doi.org/10.1002/dvdy.22573
[38] Kennedy, B.N., Stearns, G.W., Smyth, V.A., Ramamurthy, V., Van Eeden, F., Ankoudinova, I., et al. (2004) Zebrafish Rx3 and Mab21l2 Are Required during Eye Morphogenesis. Developmental Biology, 270, 336-349.
https://doi.org/10.1016/j.ydbio.2004.02.026
[39] Yamada, R., Mizutani-Koseki, Y., Koseki, H. and Takahashi, N. (2004) Requirement for Mab21l2 during Development of Murine Retina and Ventral body Wall. Developmental Biology, 274, 295-307.
https://doi.org/10.1016/j.ydbio.2004.07.016
[40] Takahashi, C., Kusakabe, M., Suzuki, T., Miyatake, K. and Nishida, E. (2015) Mab21-l3 Regulates Cell Fate Specification of Multiciliate Cells and Ionocytes. Nature Communications, 6, 6017.
https://doi.org/10.1038/ncomms7017