-
先天性免疫是机体防御病毒感染的第一道防线也是获得性免疫触发的先决条件。当病毒进入机体细胞,胞质内的感受器即被活化,而胞质感受器启动的信号最终激活STING受体,诱导产生Ⅰ型IFN和促炎性因子。2012年首次报道STING上游通路的关键分子是cGAMP,可由胞质内的cGAS催化生成,cGAMP作为人体内的第二信使,在天然免疫信号通路中发挥着重要作用。cGAMP可与接头蛋白STING结合并活化STING,进一步激活TANK结合激酶1(TBK1),诱导转录因子干扰素调节因子3(IRF3)和NF-κB入核,产生Ⅰ型IFN和细胞因子,以便机体清除入侵的病原微生物,从而防御各种病毒感染[1],维持机体健康稳态。cGAS-cGAMP-STING通路在抗病毒药物研发中的作用引起越来越多科学家的关注,本文就该通路的最新研究进展及其在抗病毒中的作用进行系统的梳理概括。
HTML
[1] | MA R, ORTIZ SERRANO T P, DAVIS J, et al. The cGAS-STING pathway: The role of self-DNA sensing in inflammatory lung disease[J]. Faseb J,2020,34(10):13156-13170. |
[2] | O'NEILL L A J. Sensing the dark side of DNA[J]. Science,2013,339(6121):763-764. |
[3] | GAO D, WU J, WU Y T, et al. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses[J]. Science,2013,341(6148):903-906. |
[4] | SWANSON K V, JUNKINS R D, KURKJIAN C J, et al. A noncanonical function of cGAMP in inflammasome priming and activation[J]. J Exp Med,2017,214(12):3611-3626. |
[5] | COHEN D, MELAMED S, MILLMAN A, et al. Cyclic GMP-AMP signalling protects bacteria against viral infection[J]. Nature,2019,574(7780):691-695. |
[6] | LI T, CHEN Z J. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer[J]. J Exp Med,2018,215(5):1287-1299. |
[7] | LI W, LU L, LU J, et al. cGAS-STING-mediated DNA sensing maintains CD8+ T cell stemness and promotes antitumor T cell therapy[J]. Sci Transl Med,2020,12(549). |
[8] | SHARMA S, SCHMID M A, SANCHEZ FELIPE L, et al. Small-molecule inhibitors of TBK1 serve as an adjuvant for a plasmid-launched live-attenuated yellow fever vaccine[J]. Hum Vaccin Immunother,2020,16(9):2196-2203. |
[9] | JIANG M, CHEN P, WANG L, et al. cGAS-STING, an important pathway in cancer immunotherapy[J]. J Hematol Oncol,2020,13(1):81. |
[10] | VOGT D, ZAVER S, RANJAN A, et al. STING is dispensable during KSHV infection of primary endothelial cells[J]. Virology,2020,540:150-159. |
[11] | WANG W, HU D, WU C, et al. STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection[J]. PLoS Pathog,2020,16(3):e1008335. |
[12] | LATIF M B, RAJA R, KESSLER P M, et al. Relative contributions of the cGAS-STING and TLR3 signaling pathways to attenuation of Herpes simplex virus 1 replication[J]. J Virol,2020,94(6):e01717-e01719. |
[13] | YOU H J, LIN Y Y, LIN F, et al. Β-catenin is required for the cGAS/STING signaling pathway but antagonized by the Herpes simplex virus 1 US3 protein[J]. J Virol,2019,94(5):1-13. |
[14] | LI D, WU R, GUO W, et al. STING-mediated IFI16 degradation negatively controls type I interferon production[J]. Cell Rep,2019,29(5):1249-1260.e4. |
[15] | ZHOU C, CHEN X, PLANELLS-CASES R, et al. Transfer of cGAMP into bystander cells via LRRC8 volume-regulated anion channels augments STING-mediated interferon responses and anti-viral immunity[J]. Immunity,2020,52(5):767-781.e6. |
[16] | LEE J K, KIM J E, PARK B J, et al. Human Cytomegalovirus IE86 protein aa 136-289 mediates STING degradation and blocks the cGAS-STING pathway[J]. J Microbiol,2020,58(1):54-60. |
[17] | LIO C W, MCDONALD B, TAKAHASHI M, et al. cGAS-STING signaling regulates initial innate control of Cytomegalovirus infection[J]. J Virol,2016,90(17):7789-7797. |
[18] | WANG J, WANG C F, MING S L, et al. Porcine IFITM1 is a host restriction factor that inhibits pseudorabies virus infection[J]. Int J Biol Macromol,2020,151:1181-1193. |
[19] | CHENG W Y, HE X B, JIA H J, et al. The cGas-sting signaling pathway is required for the innate immune response against ectromelia virus[J]. Front Immunol,2018,9:1297. |
[20] | ITO H, KANBE A, HARA A, et al. Induction of humoral and cellular immune response to HBV vaccine can be up-regulated by STING ligand[J]. Virology,2019,531:233-239. |
[21] | PÉPIN G, DE NARDO D, ROOTES C L, et al. Connexin-dependent transfer of cGAMP to phagocytes modulates antiviral responses[J]. mBio,2020,11(1). |
[22] | WANG C, GUAN Y, LV M, et al. Manganese increases the sensitivity of the cGAS-STING pathway for double-stranded DNA and is required for the host defense against DNA viruses[J]. Immunity,2018,48(4):675-687.e7. |
[23] | SU C I, KAO Y T, CHANG C C, et al. DNA-induced 2'3'-cGAMP enhances haplotype-specific human STING cleavage by dengue protease[J]. PNAS,2020,117(27):15947-15954. |
[24] | GUTJAHR A, PAPAGNO L, NICOLI F, et al. The STING ligand cGAMP potentiates the efficacy of vaccine-induced CD8+T cells[J]. JCI Insight,2019,4(7). |
[25] | HOU S, LAN X J, LI W, et al. Design, synthesis and biological evaluation of acridone analogues as novel STING receptor agonists[J]. Bioorg Chem,2020,95:103556. |
[26] | ZHANG X, LIU B, TANG L, et al. Discovery and mechanistic study of a novel human-Stimulator-of-interferon-genes agonist[J]. ACS Infect Dis,2019,5(7):1139-1149. |
[27] | LIAN H, WEI J, ZANG R, et al. ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response[J]. Nat Commun,2018,9(1):3349. |
[28] | KU J W K, CHEN Y, LIM B J W, et al. Bacterial-induced cell fusion is a danger signal triggering cGAS-STING pathway via micronuclei formation[J]. PNAS,2020,117(27):15923-15934. |
[29] | PALERMO E, ACCHIONI C, DI CARLO D, et al. Activation of latent HIV-1 T cell reservoirs with a combination of innate immune and epigenetic regulators[J]. J Virol,2019,93(21). |
[30] | DEWI PAMUNGKAS PUTRI D, KAWASAKI T, MURASE M, et al. PtdIns3P phosphatases MTMR3 and MTMR4 negatively regulate innate immune responses to DNA through modulating STING trafficking[J]. J Biol Chem,2019,294(21):8412-8423. |
[31] | GHOSH A, SHAO L, SAMPATH P, et al. Oligoadenylate-synthetase-family protein OASL inhibits activity of the DNA sensor cGAS during DNA virus infection to limit interferon production[J]. Immunity,2019,50(1):51-63.e5. |
[32] | GONG T, LIU L, JIANG W, et al. DAMP-sensing receptors in sterile inflammation and inflammatory diseases[J]. Nat Rev Immunol,2020,20(2):95-112. |
[33] | HUANG Z F, ZOU H M, LIAO B W, et al. Human Cytomegalovirus protein UL31 inhibits DNA sensing of cGAS to mediate immune evasion[J]. Cell Host Microbe,2018,24(1):69-80.e4. |
[34] | FU Y Z, GUO Y, ZOU H M, et al. Human Cytomegalovirus protein UL42 antagonizes cGAS/MITA-mediated innate antiviral response[J]. PLoS Pathog,2019,15(5):e1007691. |