Cell Host & Microbe：KSHV抗机体免疫新机制

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当DNA病毒感染宿主细胞时，其基因组DNA会被细胞内的DNA感受器cGAS识别，随后催化合成第二信使cGAMP，cGAMP通过与STING蛋白结合经信号转导激活Ⅰ型干扰素，从而启动机体的抗病毒免疫反应。


近日，来自佛罗里达州立大学的研究人员于国际杂志Cell Host & Microbe上发表了一篇研究论文，文中表示他们在DNA病毒KSHV中发现了一种特殊病毒蛋白ORF52可以抑制机体的DNA感受器cGAS，从而阻碍机体对病毒感染产生免疫反应。




卡波氏肉瘤相关疱疹病毒（Kaposi’s sarcoma-associated herpesvirus, KSHV）属于γ疱疹病毒属，是一种重要的人类肿瘤病毒，它与卡波氏肉瘤（Kaposi’s sarcoma, KS）、原发性渗出性淋巴瘤（Primary effusion lymphoma, PEL）及多中心卡斯特曼病（Multicentric Castleman Disease, MCD）等恶性疾病的发生密切相关，其中卡波氏肉瘤是艾滋病患者中常见的肿瘤及致死原因。


研究人员对KSHV病毒近90个病毒蛋白进行检测，观察是否能够抑制IFN的激活。结果发现有8中蛋白能够抑制STING-IFN信号通路，但是其中只有一个病毒蛋白ORF52能够结合DNA，推测其能够抑制胞内的DNA传感器cGAS的功能。随后的研究发现ORF52的确起到抗cGAS识别病毒DNA作用，并且是通过同时与DNA和cGAS结合来发挥抑制作用的。同时研究人员还利用反向遗传学技术构建了ORF52缺失的KSHV，与正常病毒相比，利用这一突变病毒感染细胞能够引起强烈的免疫反应。重要的是，在其他γ疱疹病毒中，ORF52的同源蛋白都发现具有cGAS抑制作用，说明这一病毒属已进化出一种相同的机制来抵抗机体的免疫反应。


这一研究发现有助于帮助解释某些DNA病毒如何逃避免疫反应，得以在机体维持长期的感染。同时也为抵抗病毒感染疾病提供新的思路和新疗法设计。




本文由中国病毒学论坛原创，欢迎转载，转载时请注明出处。

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Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein

Jian-jun Wu, Wenwei Li, Yaming Shao, Denis Avey, Bishi Fu, Joseph Gillen, Travis Hand, Siming Ma, Xia Liu, Wendell Miley, Andreas Konrad, Frank Neipel, Michael Stürzl, Denise Whitby, Hong Li, Fanxiu Zhu

Highlights
•KSHV ORF52 prevents cGAS DNA sensing by directly inhibiting cGAS enzymatic activity
•The inhibition of cGAS by ORF52 requires binding to both DNA and cGAS
•The inhibition of cGAS by ORF52 is conserved among gammaherpesviruses
•KSHV can elicit cGAS-dependent immune responses that are counteracted by ORF52

Summary
Invading viral DNA can be recognized by the host cytosolic DNA sensor, cyclic GMP-AMP (cGAMP) synthase (cGAS), resulting in production of the second messenger cGAMP, which directs the adaptor protein STING to stimulate production of type I interferons (IFNs). Although several DNA viruses are sensed by cGAS, viral strategies targeting cGAS are virtually unknown. We report here that Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, an abundant gammaherpesvirus-specific tegument protein, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity through a mechanism involving both cGAS binding and DNA binding. Moreover, ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA, suggesting conserved inhibitory mechanisms. Furthermore, KSHV infection evokes cGAS-dependent responses that can limit the infection, and an ORF52 null mutant exhibits increased cGAS signaling. Our findings reveal a mechanism through which gammaherpesviruses antagonize host cGAS DNA sensing.

http://www.cell.com/cell-host-microbe/abstract/S1931-3128(15)00307-8

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