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InvivoGen帶您讀文獻(xiàn)之“STING與病毒防御”

2021-05-11
瀏覽次數(shù): 121

InvivoGen帶您讀文獻(xiàn)之“STING與病毒防御”



天然免疫是宿主的第一道防線。站在“長(zhǎng)城”上的天然免疫感受器實(shí)時(shí)監(jiān)控并識(shí)別外來(lái)入侵的病原微生物,并啟動(dòng)抗微生物免疫應(yīng)答。當(dāng)微生物進(jìn)入宿主細(xì)胞,活化不同的胞漿感受器,而由不同的胞漿感受器啟動(dòng)的信號(hào)最終都被STING受體接收,后者誘導(dǎo)產(chǎn)生I型干擾素和促炎性細(xì)胞因子。隨著STING抗病毒應(yīng)答研究的深入,更多的疑問(wèn)也被提出,例如STING是如何與不同胞漿核酸感受器或適配器協(xié)同完成抗病毒免疫應(yīng)答InvivoGen公司提供全系列STING相關(guān)產(chǎn)品,協(xié)助您深入開(kāi)展STING研究。


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InvivoGen提供的STING相關(guān)產(chǎn)品

STING 配體: 2’3’-cGAMP - 3’3’-cGAMP - c-di-GMP - c-di-AMP …

STING 變異株: STING-WT - hSTING-HAQ - hSTING-H232 …

STING 敲除細(xì)胞:RAW-Lucia??ISG-KO-STING Cells - THP1-Dual KO-STING Cells…

STING 報(bào)告基因細(xì)胞系:RAW-Lucia??ISG Cells - THP1-Blue??ISG Cells …

ELISA 試劑盒:LumiKine? Xpress hIFN-α - LumiKine? Xpress hIFN-β

更多產(chǎn)品信息,請(qǐng)?jiān)L問(wèn)www.invivogen.cn

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STING 與病毒防御-

宿主細(xì)胞接觸病毒后會(huì)立即啟動(dòng)天然免疫應(yīng)答,包括誘導(dǎo)產(chǎn)生I型干擾素和促炎性細(xì)胞因子,以便清除入侵的病原。最近研究發(fā)現(xiàn),在病毒感染后,可被細(xì)胞內(nèi)受體IFI16,cGAS和STING識(shí)別并激活I(lǐng)型干擾素信號(hào)通路,這樣的防御機(jī)制涵蓋DNA病毒和RNA病毒。研究HSV-1和CMV等DNA病毒時(shí)發(fā)現(xiàn),病毒基因組DNA可以結(jié)合DNA感受器-IFI16和cGAS,從而揭示了外源基因組的DNA識(shí)別機(jī)制[1,13]。研究證明病毒感染宿主細(xì)胞后,將其基因組DNA被釋放到細(xì)胞內(nèi),后者可激活STING-TBK1依賴的免疫應(yīng)答[2,3,4]也有研究指出,病毒感染后可以引起細(xì)胞應(yīng)激,觸發(fā)線粒體釋放DNA到胞漿,活化cGAS-STING信號(hào)通路[22]。隨著研究的深入與拓展,科研人員發(fā)現(xiàn)STING在RNA病毒應(yīng)答中也扮演重要角色。過(guò)表達(dá)STING可以抑制新城疫病毒和禽流感病毒的復(fù)制,而這個(gè)防御機(jī)制并不依賴于RIG-I和cGAS[5,6]。敲底STING的表達(dá)水平,也可以提高登革熱病毒的復(fù)制[7,8]。丙型肝炎病毒調(diào)節(jié)STING的應(yīng)答機(jī)制雖然存在一些小的爭(zhēng)議,不過(guò)可以確定的是,丙型肝炎病毒刺激STING敲除的細(xì)胞并不能引起I型干擾素的產(chǎn)生[9,10]。RNA病毒也存在一些含有DNA的核酸結(jié)構(gòu),逆轉(zhuǎn)錄病毒在復(fù)制過(guò)程中產(chǎn)生的反轉(zhuǎn)錄DNA中間體如RNA:DNA,單鏈DNA,亦激活DNA感受器。HIV-1在侵染細(xì)胞中釋放的單鏈DNA可被cGAS識(shí)別,激活I型干擾素[11, 23]。在病毒感染過(guò)程中,不同來(lái)源的DNA活化cGAS-STING通路的機(jī)制還需要進(jìn)一步探明。 ???

越來(lái)越多的跡象表明,被感染的細(xì)胞不僅可以識(shí)別DNA完成自身防御,同時(shí)將cGAMP通過(guò)縫隙連接(gap junction)傳遞到臨近細(xì)胞,從而激活STING依賴的I型干擾素表達(dá)[24];另外,有報(bào)道指出病毒顆??裳b配cGAMP,從而傳遞并激活天然免疫應(yīng)答[25]。以上研究揭示了STING在病毒防御中的核心作用,為預(yù)防或治療傳染性疾病提供新線索。


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STING 與病毒拮抗免疫防御策略-

在病毒和免疫系統(tǒng)共同進(jìn)化的壓力下,病毒學(xué)會(huì)了如何與免疫系統(tǒng)對(duì)抗并成功入侵宿主的技能。抑制I型干擾素應(yīng)答是病毒入侵的關(guān)鍵機(jī)制。據(jù)報(bào)道,皰疹病毒家族通過(guò)不同的策略抑制STING-TBK1信號(hào)通路,如降解或鎖住IFI16[4,13];抑制cGAS的酶活性[15];或抑制STING和TBK1的相互作用[16]。其它病毒也有對(duì)應(yīng)STING通路的抑制策略。乙型肝炎病毒可以促使STING降解從而抑制其功能[17]。DNA腫瘤病毒中,乳頭瘤病毒的E7蛋白和腺病毒的E1A蛋白可拮抗cGAS-STING通路,從而抑制免疫應(yīng)答[19]。DNA病毒外,RNA病毒也具有調(diào)劑STING的能力。雖然這看起來(lái)違背常理,不過(guò)已發(fā)表的數(shù)據(jù)表明RNA病毒具有不同的抑制STING應(yīng)答方式。登革熱病毒編碼的NS2B3蛋白酶可作用于人源STING的氨基酸末端,裂解人源STING,而鼠源STING對(duì)NS2B3蛋白酶具有抗性 [7,8]。丙型肝炎病毒編碼的NS4B蛋白可阻斷STING和TBK1的相互作用[10];A型流感病毒的血凝素蛋白可阻止STING二聚體形成[6]; HIV干擾STING與TBK1的相互作用[21]。隨著科研工作的深入,病毒逃避免疫識(shí)別的機(jī)制也逐漸清晰,研究重點(diǎn)需轉(zhuǎn)向關(guān)于體內(nèi)(in vivo)的感染機(jī)制。隨著對(duì)致病性病毒疾病的認(rèn)知不斷積累,病毒感染細(xì)胞的作用靶點(diǎn)以及病毒逃避免疫防御的機(jī)制都是未來(lái)抗病毒新藥研發(fā)的參考依據(jù)。


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1. Horan KA, et al. 2013.Proteasomal degradation of herpes simplex virus capsids in macrophages releases DNA to the cytosol for recognition by DNA sensors. J Immunol.

2. Lam E1,?et al. 2014.?Adenovirus detection by the cGAS/STING/TBK1 DNA sensing cascade.?J Virol.

3. Victor R. DeFilippis, et al. 2010.Human Cytomegalovirus Induces the Interferon Response via the DNA Sensor ZBP1. J Virol.

4. Li T, et al. 2013.?Human cytomegalovirus tegument protein pUL83 inhibits IFI16-mediated DNA sensing for immune evasion. Cell Host Microbe.

5. Yuqiang Cheng, et al. 2015.Chicken STING Mediates Activation of the IFN Gene Independently of the RIG-I Gene. J Immunol.

6. Christian K. Holm. et al. 2016.Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses. Nat commun.

7. Chia-Yi Yu, et al. 2012. Dengue Virus Targets the Adaptor Protein MITA to Subvert Host Innate Immunity. PLoS Path.

8. Sebastian Aguirre, et al. 2012.DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING. PLoS Path.

9. Nitta S, et al. 2013.?Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type-I interferon-dependent innate immunity. Hepatology.

10. Qiang Ding, et. al. 2013. Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity. J Hepatol.

11. Daxing Gao, et. al. 2013.Cyclic GMP-AMP Synthase Is an Innate Immune Sensor of HIV and Other Retroviruses. Science.

12. Sunnie M. Yoh, et. al. 2015.PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1. Cell.

13. Orzalli MH, et al. 2012. ?Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein. PNAS.

14. Maria H Christensen, et al. 2016. HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression. The EMBO Journal.

15. Wu JJ, et al. 2015. Inhibition of cGAS DNA sensing by a herpesvirus virion protein. Cell Host Microbe.

16.?Ma Z, et al. Modulation of the cGAS-STING DNA sensing pathway by gammaher- pesviruses. PNAS 2015.

17. LiuY, et al. 2015. Hepatitis B virus polymerase disrupts K63-linked ubiquitination of STING to block innate cytosolic DNA-sensing pathways. J Virol.

18. McLaughlin-Drubin ME, Munger K. 2009. The human papillomavirus E7 oncoprotein. Virology.

19. Laura L, et al. 2015. ?DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science.

20.?Xing Y, et al. 2013. The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase. J Gen Virol.

21. Haitao Guo, et al. 2016. NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses. Cell Host & Microbe.

22. West AP, et al. 2015. ?Mitochondrial DNA stress primes the antiviral innate immune response. Nature.

23. Herzner AM, et al. 2015. Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA. Nat Immunol.

24. Ablasser A, et al. 2013. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature.

25. Gentili M, et al. 2015. Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science.



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