OASes and STING: adaptive evolution in concert.
OASes and STING: adaptive evolution in concert.
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DOI：
10.1093/gbe/evv046
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发表时间：
2015-03-09
影响因子：
3.3
通讯作者：
Sironi M
中科院分区：
文献类型：
--
作者：
Mozzi A;Pontremoli C;Forni D;Clerici M;Pozzoli U;Bresolin N;Cagliani R;Sironi M
OAS（2 ' -5 ' -寡腺苷酸合成酶）蛋白和环GMP-AMP合成酶（cGAS，基因符号：MB21D1）在细胞质中巡逻，寻找外源核酸的存在。与双链RNA或双链DNA结合后，OAS蛋白和cGAS产生核苷酸第二信使，分别激活RNase L和STING（干扰素基因刺激因子，基因符号：TMEM173）；这导致抗病毒反应的启动。我们分析了灵长类动物和蝙蝠的MB21D1-TMEM173和OAS-RNASEL轴的进化史，发现这两个目中存在广泛的正向选择的证据。在TMEM173中，残基230是灵长类动物和翼翅目动物对天然配体和模拟药物（如DMXAA）反应的主要决定因素。在这两个序列中，选择也针对RNase L中的α-螺旋/环元件，该元件调节酶对单链RNA和茎环的偏好。对OAS1、OAS2和MB21D1中正选择位点的分析显示，它们的进化是平行的，在不同的基因中选择了相应的残基。由于这不是基因转化的结果，这些数据表明，作用于OAS和MB21D1基因的选择压力与核酸识别和酶激活的特定机制有关，而酶激活需要发生构象变化。最后，对人类、黑猩猩和大猩猩的种群遗传系统发育分析发现，在大多数基因中存在几个正选择位点。这里的数据揭示了感染易感性和对合成化合物反应的物种特异性差异，与合成化合物作为疫苗佐剂的设计相关。
OAS (2′–5′-oligoadenylate synthases) proteins and cyclic GMP–AMP synthase (cGAS, gene symbol: MB21D1) patrol the cytoplasm for the presence of foreign nucleic acids. Upon binding to double-stranded RNA or double-stranded DNA, OAS proteins and cGAS produce nucleotide second messengers to activate RNase L and STING (stimulator of interferon genes, gene symbol: TMEM173), respectively; this leads to the initiation of antiviral responses. We analyzed the evolutionary history of the MB21D1–TMEM173 and OAS–RNASEL axes in primates and bats and found evidence of widespread positive selection in both orders. In TMEM173, residue 230, a major determinant of response to natural ligands and to mimetic drugs (e.g., DMXAA), was positively selected in Primates and Chiroptera. In both orders, selection also targeted an α-helix/loop element in RNase L that modulates the enzyme preference for single-stranded RNA versus stem loops. Analysis of positively selected sites in OAS1, OAS2, and MB21D1 revealed parallel evolution, with the corresponding residues being selected in different genes. As this cannot result from gene conversion, these data suggest that selective pressure acting on OAS and MB21D1 genes is related to nucleic acid recognition and to the specific mechanism of enzyme activation, which requires a conformational change. Finally, a population genetics-phylogenetics analysis in humans, chimpanzees, and gorillas detected several positively selected sites in most genes. Data herein shed light into species-specific differences in infection susceptibility and in response to synthetic compounds, with relevance for the design of synthetic compounds as vaccine adjuvants.
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影响因子：
64.8
作者：
通讯作者：
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古代和最近的选择性压力在AIM2样核酸传感器上塑造了遗传多样性。
影响因子：
3.3
作者：
Cagliani R;Forni D;Biasin M;Comabella M;Guerini FR;Riva S;Pozzoli U;Agliardi C;Caputo D;Malhotra S;Montalban X;Bresolin N;Clerici M;Sironi M
通讯作者：
Sironi M
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
32.4
作者：
Forni, Diego;Cagliani, Rachele;Sironi, Manuela
通讯作者：
Sironi, Manuela
影响因子：
3.7
作者：
Lemos de Matos A;McFadden G;Esteves PJ
通讯作者：
Esteves PJ