He Zhiheng, Zhao Jun, Zhang Junjie, Jung Jae U, Feng Pinghui
Department of Molecular Microbiology and Immunology, Keck Medical Center, University of Southern California, Los Angeles, California, USA.
J Virol. 2014 Jan;88(1):444-55. doi: 10.1128/JVI.01716-13. Epub 2013 Oct 23.
All herpesviruses share a remarkable propensity to establish latent infection. Human Kaposi's sarcoma-associated herpesvirus (KSHV) effectively enters latency after de novo infection, suggesting that KSHV has evolved with strategies to facilitate latent infection. NF-κB activation is imperative for latent infection of gammaherpesviruses. However, how NF-κB is activated during de novo herpesvirus infection is not fully understood. Here, we report that KSHV infection activates the inhibitor of κB kinase β (IKKβ) and the IKK-related kinase epsilon (IKKε) to enable host NF-κB activation and KSHV latent infection. Specifically, KSHV infection activated IKKβ and IKKε that were crucial for latent infection. Knockdown of IKKβ and IKKε caused aberrant lytic gene expression and impaired KSHV latent infection. Biochemical and genetic experiments identified RelA as a key player downstream of IKKβ and IKKε. Remarkably, IKKβ and IKKε were essential for phosphorylation of S(536) and S(468) of RelA, respectively. Phosphorylation of RelA S(536) was required for phosphorylation of S(468), which activated NF-κB and promoted KSHV latent infection. Expression of the phosphorylation-resistant RelA S(536)A increased KSHV lytic gene expression and impaired latent infection. Our findings uncover a scheme wherein NF-κB activation is coordinated by IKKβ and IKKε, which sequentially phosphorylate RelA in a site-specific manner to enable latent infection after KSHV de novo infection.
所有疱疹病毒都具有建立潜伏感染的显著倾向。人类卡波西肉瘤相关疱疹病毒（KSHV）在初次感染后能有效进入潜伏状态，这表明KSHV已进化出促进潜伏感染的策略。NF-κB激活对于γ疱疹病毒的潜伏感染至关重要。然而，在疱疹病毒初次感染期间NF-κB如何被激活尚不完全清楚。在此，我们报道KSHV感染激活κB激酶β（IKKβ）抑制剂和IKK相关激酶ε（IKKε），从而使宿主NF-κB激活及KSHV潜伏感染。具体而言，KSHV感染激活了对潜伏感染至关重要的IKKβ和IKKε。敲低IKKβ和IKKε会导致异常的裂解基因表达并损害KSHV潜伏感染。生化和遗传学实验确定RelA是IKKβ和IKKε下游的关键因子。值得注意的是，IKKβ和IKKε分别对RelA的S(536)和S(468)磷酸化至关重要。RelA S(536)的磷酸化是S(468)磷酸化所必需的，后者激活NF-κB并促进KSHV潜伏感染。抗磷酸化的RelA S(536)A的表达增加了KSHV裂解基因表达并损害了潜伏感染。我们的研究结果揭示了一种机制，其中NF-κB激活由IKKβ和IKKε协调，它们以位点特异性方式依次磷酸化RelA，从而在KSHV初次感染后实现潜伏感染。
