108 : Preventing activation of the IFN inducible OAS-RNase L pathway by A-kinase anchoring protein 7 (AKAP7)
108 : Preventing activation of the IFN inducible OAS-RNase L pathway by A-kinase anchoring protein 7 (AKAP7)
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DOI：
10.1016/j.cyto.2013.06.111
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发表时间：
2013-08-14
期刊：
影响因子：
3.8
通讯作者：
H. Silverman R
中科院分区：
文献类型：
--
作者：
Gusho E;Jha BK;Zhang R;Weiss SR;H. Silverman R
2‘，5’-寡腺苷(2-5A)合成酶-核糖核酸酶L系统是一种干扰素诱导途径，通过裂解病毒和细胞单链核糖核酸来阻断病毒感染。病毒双链RNA在核糖核酸和脱氧核糖核酸感染过程中产生，激活病原体识别受体OAS(病原体识别受体)，导致三磷酸腺苷产生2-5A，然后激活核糖核酸酶L，导致核糖核酸切割。决定细胞如何限制OAS-核糖核酸酶L通路的激活以避免组织损伤的因素还知之甚少。最近，我们报道了冠状病毒，小鼠肝炎病毒A59株的辅助蛋白NS2，阻断巨噬细胞中的核糖核酸酶L途径，促进肝炎的发生(赵等，细胞宿主与微生物11：607-16,2012)。NS2蛋白是一个2H磷酸酯酶家族成员，具有两个保守的His-x-Thr/Ser基序，通过其2‘，5’-磷酸二酯酶活性消除核糖核酸酶L的激活因子2-5A。在这里，我们将展示细胞A-激酶锚定蛋白7(AKAP7)，另一种2H磷酸酯酶和NS2的同源物，具有类似的降解2-5A的酶活性。因此，AKAP7潜在地为宿主细胞提供了一种消除过剩的2-5A从而终止核糖核酸酶L激活的机制。因此，核糖核酸酶L介导的rRNA切割响应聚(RI)：聚(RC)激活OAS被AKAP7抑制，如RNA芯片分析所确定的。此外，通过荧光共振能量转移检测核糖核酸酶L的激活，AKAP7的表达降低了细胞活性2-5A的水平。这些发现表明，AKAP7可能通过阻止RNaseL的持续激活而起到细胞保护作用。
The 2′,5′-oligoadenylate (2-5A) synthetase (OAS)-RNase L system is an interferon inducible pathway that blocks virus infections by cleaving viral and cellular single-stranded RNA. Viral dsRNA, produced during infections by both RNA and DNA viruses, activates OAS (a pathogen recognition receptor) resulting in production of 2-5A from ATP, which then activates RNase L leading to RNA cleavage. The factors that determine how cells limit activation of OAS-RNase L pathway to avoid tissue damage are poorly understood. Recently, we reported that the coronavirus, murine hepatitis virus (MHV) strain A59 accessory protein, ns2, blocks the RNase L pathway in macrophages and facilitates the development of hepatitis (Zhao et al., Cell Host & Microbe 11:607–16, 2012). The ns2 protein is a 2H phosphoesterase family member with two conserved His-x-Thr/Ser motifs that eliminates 2-5A, the activator of RNase L, through its 2′,5′-phosphodiesterase activity. Here we will show that cellular A-kinase anchoring protein 7 (AKAP7), another 2H phosphoesterase and homolog of ns2, has a similar enzymatic activity that degrades 2-5A. AKAP7 thus potentially provides the host cell with a mechanism for eliminating excess 2-5A and thus terminating RNase L activation. Accordingly, RNase L-mediated cleavage of rRNA in response to poly (rI):poly (rC) activation of OAS was suppressed by AKAP7 as determined in RNA chip analyses. In addition, cellular levels of active 2-5A were reduced by AKAP7 expression as determined by fluorescence resonance energy transfer assays for RNase L activation. These findings suggest that AKAP7 may be cytoprotective by preventing sustained activation of RNase L.