Histone Demethylase JMJD2A Regulates Kaposi's Sarcoma-Associated Herpesvirus Replication and Is Targeted by a Viral Transcriptional Factor
Histone Demethylase JMJD2A Regulates Kaposi's Sarcoma-Associated Herpesvirus Replication and Is Targeted by a Viral Transcriptional Factor
复制标题
DOI：
10.1128/jvi.02485-10
复制
发表时间：
2011-04-01
影响因子：
5.4
通讯作者：
Kung, Hsing-Jien
中科院分区：
文献类型：
--
作者：
Chang, Pei-Ching;Fitzgerald, Latricia D.;Kung, Hsing-Jien
卡波西肉瘤相关疱疹病毒（KSHV）的潜伏期和裂解周期之间的转换伴随着组蛋白编码的特定改变。最近，对KSHV组蛋白修饰的综合分析显示，H3 K27 me 3在KSHV基因组中沉积，其中两个特定区域被异染色质标记H3 K9 me 3占据。在这里，我们表明，敲低JMJD 2A，一种H3 K9 me 3脱甲基酶，减弱病毒滴度，而其过表达增加KSHV再活化。JMJD 2A定位于H3 K9 me 3标记缺陷的潜伏病毒染色体区域，表明JMJD 2A可能是病毒染色质上该标记水平低的原因。潜伏基因组上JMJD 2A的存在使H3 K9保持未甲基化形式，并发出特定病毒基因组准备重新激活的信号。JMJD 2A的脱甲基酶活性对于KSHV的再活化是重要的，因为脱甲基酶缺陷突变体不能恢复JMJD 2A敲低表型。有趣的是，我们发现KSHV编码与JMJD 2A相关的K-bZIP，导致在体内和体外抑制JMJD 2A的脱甲基酶活性。K-bZIP对JMJD 2A的抑制可能是由于阻断底物可及性的物理相互作用。这种抑制的结果是增加H3 K9 me 3和基因沉默的总体水平。一致地，与未诱导的对照细胞的结果相比，K-bZIP过表达导致对>= 2倍差异调节基因的抑制类似于80%。将讨论在病毒复制期间K-bZIP靶向JMJD 2A的后果。据我们所知，这是第一个描述的病毒产品显示是一个有效的抑制剂宿主细胞组蛋白去甲基化酶。
The switch between the latency and lytic cycles of Kaposi's sarcoma-associated herpesvirus (KSHV) is accompanied by specific alterations of histone codes. Recently, comprehensive analysis of histone modifications of KSHV showed the deposition of H3K27me3 across the KSHV genome with two specific regions occupied by the heterochromatin marker H3K9me3. Here, we show that knockdown of JMJD2A, an H3K9me3 demethylase, attenuates viral titers, whereas its overexpression increases KSHV reactivation. JMJD2A is localized in regions of latent viral chromosomes that are deficient in the H3K9me3 mark, indicating that JMJD2A may be responsible for the low level of this mark on viral chromatin. The presence of JMJD2A on the latent genome maintains H3K9 in unmethylated form and signals the readiness of specific sets of viral genes to be reactivated. The demethylase activity of JMJD2A is important for KSHV reactivation, because a demethylase-deficient mutant cannot restore the JMJD2A knockdown phenotype. Interestingly, we found that the KSHV encoded K-bZIP associated with JMJD2A, resulting in the inhibition of demethylase activity of JMJD2A both in vivo and in vitro. Inhibition of JMJD2A by K-bZIP is likely due to a physical interaction which blocks substrate accessibility. A consequence of such an inhibition is increasing global levels of H3K9me3 and gene silencing. Consistently, K-bZIP overexpression resulted in a repression of similar to 80% of the >= 2-fold differentially regulated genes compared to results for the uninduced control cells. The consequences of K-bZIP targeting JMJD2A during viral replication will be discussed. To our knowledge, this is the first description of a viral product shown to be a potent inhibitor of a host cellular histone demethylase.