Darrah Eric J, Stoltz Kyle P, Ledwith Mitchell, Tarakanova Vera L
Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States.
Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States; Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States.
Virology. 2017 Oct;510:137-146. doi: 10.1016/j.virol.2017.07.014. Epub 2017 Jul 18.
Ataxia-Telangiectasia mutated (ATM) kinase participates in multiple networks, including DNA damage response, oxidative stress, and mitophagy. ATM also supports replication of diverse DNA and RNA viruses. Gammaherpesviruses are prevalent cancer-associated viruses that benefit from ATM expression during replication. This proviral role of ATM had been ascribed to its signaling within the DNA damage response network; other functions of ATM have not been considered. In this study increased type I interferon (IFN) responses were observed in ATM deficient gammaherpesvirus-infected macrophages. Using a mouse model that combines ATM and type I IFN receptor deficiencies we show that increased type I IFN response in the absence of ATM fully accounts for the proviral role of ATM during gammaherpesvirus replication. Further, increased type I IFN response rendered ATM deficient macrophages more susceptible to antiviral effects of type II IFN. This study identifies attenuation of type I IFN responses as the primary mechanism underlying proviral function of ATM during gammaherpesvirus infection.
共济失调毛细血管扩张症突变（ATM）激酶参与多个网络，包括DNA损伤反应、氧化应激和线粒体自噬。ATM还支持多种DNA和RNA病毒的复制。γ疱疹病毒是普遍存在的与癌症相关的病毒，在复制过程中受益于ATM的表达。ATM的这种前病毒作用归因于其在DNA损伤反应网络中的信号传导；尚未考虑ATM的其他功能。在本研究中，在ATM缺陷的γ疱疹病毒感染的巨噬细胞中观察到I型干扰素（IFN）反应增加。使用结合了ATM和I型IFN受体缺陷的小鼠模型，我们表明在没有ATM的情况下I型IFN反应增加完全解释了ATM在γ疱疹病毒复制过程中的前病毒作用。此外，I型IFN反应增加使ATM缺陷的巨噬细胞更容易受到II型IFN的抗病毒作用。本研究确定I型IFN反应减弱是γ疱疹病毒感染期间ATM前病毒功能的主要机制。
