African Swine Fever Virus EP364R and C129R Target Cyclic GMP-AMP To Inhibit the cGAS-STING Signaling Pathway.
African Swine Fever Virus EP364R and C129R Target Cyclic GMP-AMP To Inhibit the cGAS-STING Signaling Pathway.
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DOI：
10.1128/jvi.01022-22
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发表时间：
2022-08-10
影响因子：
5.4
通讯作者：
Lee, Jong-Soo
中科院分区：
文献类型：
--
作者：
Dodantenna, Niranjan;Ranathunga, Lakmal;Chathuranga, W. A. Gayan;Weerawardhana, Asela;Cha, Ji-Won;Subasinghe, Ashan;Gamage, Nuwan;Haluwana, D. K.;Kim, YongKwan;Jheong, WeonHwa;Poo, Haryoung;Lee, Jong-Soo
非洲猪瘟病毒(ASFV)是一种高致病性的猪DNA病毒，可引起家猪和野猪的非洲猪瘟(ASF)。为了有效地感染病毒，ASFV开发了复杂的策略来逃避抗病毒先天免疫反应的关键成分。然而，ASFV的免疫逃逸机制尚不清楚。在ASFV感染后，胞质DNA传感器环状GMP-AMP(2‘，3’-cGAMP)合成酶(CGAS)识别ASFV DNA并合成第二信使2‘，3’-cGAMP，该信使触发干扰素的产生以干扰病毒的复制。在这项研究中，我们展示了ASFV EP364R和C129R的一种新的免疫逃避机制，它阻断了细胞周期2‘，3’-cGAMP介导的抗病毒反应。与核酸酶同源的ASFV EP364R和C129R通过与2‘，3’-cGAMP特异性相互作用，发挥其磷酸二酯酶(PDE)活性来裂解2‘，3’-cGAMP，从而抑制干扰素介导的反应。尤其值得注意的是，ASFV EP364R与含有2‘，3’-cGAMP结合基序的干扰素基因刺激物(STING)蛋白有一个同源性区域，以及EP364R的Y76S和N78A氨基酸的点突变，这些突变削弱了与2‘，3’-cGAMP的相互作用，并恢复了随后的抗病毒反应。这些结果强调了ASFV EP364R和C129R在抑制干扰素应答中的关键作用，并可用于开发ASFV减毒活疫苗。非洲猪瘟(ASF)是由非洲猪瘟病毒(ASFV)引起的家猪和野猪的一种高度传染性出血性疾病。ASF是全球养猪业的一种致命流行病，但目前还没有药物或疫苗可用。了解ASFV的致病机理是研制有效的ASFV减毒活疫苗的基础，研究ASFV的免疫逃逸机制对提高对其致病机理的认识至关重要。在这项研究中，我们首次鉴定了EP364R和C129R，这是一种抑制I型干扰素信号的未知蛋白质。ASFV EP364R和C129R与哺乳动物第二信使2‘，3’-cGAMP特异性结合，发挥磷酸二酯酶活性裂解2‘，3’-cGAMP。在这项研究中，我们发现了ASFV抑制干扰素介导的抗病毒反应的新机制，我们的发现可以指导ASFV致病机理的理解和ASFV减毒活疫苗的开发。
African swine fever virus (ASFV) is a highly pathogenic swine DNA virus with high mortality that causes African swine fever (ASF) in domestic pigs and wild boars. For efficient viral infection, ASFV has developed complex strategies to evade key components of antiviral innate immune responses. However, the immune escape mechanism of ASFV remains unclear. Upon ASFV infection, cyclic GMP-AMP (2′,3′-cGAMP) synthase (cGAS), a cytosolic DNA sensor, recognizes ASFV DNA and synthesizes the second messenger 2′,3′-cGAMP, which triggers interferon (IFN) production to interfere with viral replication. In this study, we demonstrated a novel immune evasion mechanism of ASFV EP364R and C129R, which blocks cellular cyclic 2′,3′-cGAMP-mediated antiviral responses. ASFV EP364R and C129R with nuclease homology inhibit IFN-mediated responses by specifically interacting with 2′,3′-cGAMP and exerting their phosphodiesterase (PDE) activity to cleave 2′,3′-cGAMP. Particularly notable is that ASFV EP364R had a region of homology with the stimulator of interferon genes (STING) protein containing a 2′,3′-cGAMP-binding motif and point mutations in the Y76S and N78A amino acids of EP364R that impaired interaction with 2′,3′-cGAMP and restored subsequent antiviral responses. These results highlight a critical role for ASFV EP364R and C129R in the inhibition of IFN responses and could be used to develop ASFV live attenuated vaccines. IMPORTANCE African swine fever (ASF) is a highly contagious hemorrhagic disease in domestic pigs and wild boars caused by African swine fever virus (ASFV). ASF is a deadly epidemic disease in the global pig industry, but no drugs or vaccines are available. Understanding the pathogenesis of ASFV is essential to developing an effective live attenuated ASFV vaccine, and investigating the immune evasion mechanisms of ASFV is crucial to improve the understanding of its pathogenesis. In this study, for the first time, we identified the EP364R and C129R, uncharacterized proteins that inhibit type I interferon signaling. ASFV EP364R and C129R specifically interacted with 2′,3′-cGAMP, the mammalian second messenger, and exerted phosphodiesterase activity to cleave 2′,3′-cGAMP. In this study, we discovered a novel mechanism by which ASFV inhibits IFN-mediated antiviral responses, and our findings can guide the understanding of ASFV pathogenesis and the development of live attenuated ASFV vaccines.
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DOI：
10.3390/v13010077
发表时间：
2021-01-08
期刊：
Viruses
影响因子：
--
作者：
Aicher SM;Monaghan P;Netherton CL;Hawes PC
通讯作者：
Hawes PC
DOI：
10.1073/pnas.050585197
发表时间：
2000-03-28
影响因子：
11.1
作者：
Fawcett, L;Baxendale, R;Phillips, SC
通讯作者：
Phillips, SC
影响因子：
5.4
作者：
Alejo, Alf;Matamoros, Tania;Andres, German
通讯作者：
Andres, German
影响因子：
22.7
作者：
Carozza JA;Böhnert V;Nguyen KC;Skariah G;Shaw KE;Brown JA;Rafat M;von Eyben R;Graves EE;Glenn JS;Smith M;Li L
通讯作者：
Li L
DOI：
10.1007/978-1-4939-7240-1_25
发表时间：
2017
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Chambers JR;Sauer K
通讯作者：
Sauer K