Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS
Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS
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DOI：
10.1073/pnas.1516812113
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发表时间：
2016-02-23
影响因子：
11.1
通讯作者：
Schulz, Thomas F.
中科院分区：
文献类型：
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作者：
Zhang, Guigen;Chan, Baca;Schulz, Thomas F.
卡波西肉瘤疱疹病毒（Kaposi sarcoma herpesvirus，KSHV）的潜伏相关核抗原（latency-associated nuclear antigen，拉娜）主要定位于潜伏感染细胞的细胞核内，在病毒游离DNA的复制和维持中起关键作用。此外，已报道了由内部翻译起始引起的拉娜的N-末端截短的胞质同种型，但其功能尚不清楚。使用免疫共沉淀和MS，我们发现cGMP-AMP合酶（cGAS），先天免疫DNA传感器，是细胞质拉娜亚型的细胞相互作用伙伴。通过直接结合cGAS，拉娜，特别是细胞质同种型，抑制TBK 1和IRF 3的cGAS-STING依赖性磷酸化，从而拮抗cGAS介导的KSHV裂解复制的限制。我们假设胞质形式的拉娜（其表达在裂解复制期间增加）抑制cGAS以促进KSHV从潜伏期重新激活。这一观察结果指出了裂解复制过程中拉娜的细胞质同种型的新功能，并将拉娜的功能从其在潜伏期至裂解复制周期期间的作用扩展。
The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING-dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGAS-mediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle.