Deregulation of KSHV latency conformation by ER-stress and caspase-dependent RAD21-cleavage.
Deregulation of KSHV latency conformation by ER-stress and caspase-dependent RAD21-cleavage.
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DOI：
10.1371/journal.ppat.1006596
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发表时间：
2017-08
期刊：
影响因子：
6.7
通讯作者：
Lieberman PM
中科院分区：
文献类型：
--
作者：
De Leo A;Chen HS;Hu CC;Lieberman PM
卡波西肉瘤（KS）相关疱疹病毒（KSHV）是一种人类γ疱疹病毒，被认为是KS和原发性渗出性淋巴瘤（PEL）的主要病原体。KSHV在B淋巴细胞中建立持续的潜伏感染，其中病毒基因表达部分受到粘着蛋白依赖性染色体构象的限制。在这里，我们表明，内质网（ER）的压力诱导一个快速的，半胱天冬酶依赖的切割的粘附素亚基RAD21。ER应激诱导的RAD21裂解与快速和强烈的病毒裂解转录激活相关。在几种KSHV阳性PEL细胞中观察到这种效应，但在KSHV潜伏期的其他B细胞或非B细胞模型中未观察到这种效应。切割的RAD21不从病毒基因组解离，也不从粘附素复合物的其他组分分解。然而，RAD21切割与潜伏基因组构象的破坏相关，如染色体构象捕获所揭示的（3C）。在BCBLI细胞中，外源性表达的C端切割型的RAD21可部分诱导KSHV裂解基因的转录，提示ER应激诱导的RAD21切割足以诱导KSHV从潜伏状态重新激活。总之，我们的研究结果揭示了一个新的方面控制和维持KSHV基因组潜伏构象介导的压力诱导的RAD21切割。我们的研究还表明，RAD21切割可能是一个通用的调节机制，快速改变细胞染色体构象和粘着蛋白依赖的转录调控。卡波西肉瘤（KS）相关疱疹病毒（KSHV）的潜伏感染与宿主细胞的恶性转化有关。KSHV相关性胸腔积液淋巴瘤（PEL）对内质网（ER）应激高度敏感，这是由于ER应激反应途径的潜在缺陷。我们在这里表明，ER应激诱导剂导致KSHV裂解转录物的快速激活，并在caspase和钙蛋白酶依赖的蛋白水解裂解的RAD 21中发现了一个潜在的机制。RAD21是粘附素复合物的亚基，其维持限制KSHV裂解周期转录的染色体构象。ER应激诱导的RAD21裂解改变了与潜伏期相关的KSHV染色体构象，以及RNA聚合酶II相关和激活的位点特异性增加。这些发现为KSHV潜伏期的调节及其对ER应激的反应提供了新的见解，并可能进一步发展KSHV相关PEL和相关恶性肿瘤的选择性治疗。
Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is a human gammaherpesvirus recognized as the principal causative agent of KS and primary effusion lymphoma (PEL). KSHV establishes persistent latent infection in B lymphocytes where viral gene expression is restricted, in part, by a cohesin-dependent chromosome conformation. Here, we show that endoplasmic reticulum (ER) stress induces a rapid, caspase-dependent cleavage of cohesin subunit RAD21. ER stress-induced cleavage of RAD21 correlated with a rapid and strong viral lytic transcriptional activation. This effect was observed in several KSHV positive PEL cells, but not in other B-cells or non-B-cell models of KSHV latency. The cleaved-RAD21 does not dissociate from viral genomes, nor disassemble from other components of the cohesin complex. However, RAD21 cleavage correlated with the disruption of the latency genome conformation as revealed by chromosome conformation capture (3C). Ectopic expression of C-terminal RAD21 cleaved form could partially induce KSHV lytic genes transcription in BCBLI cells, suggesting that ER-stress induced RAD21 cleavage was sufficient to induce KSHV reactivation from latency in PEL cells. Taken together our results reveal a novel aspect for control and maintenance of KSHV genome latency conformation mediated by stress-induced RAD21 cleavage. Our studies also suggest that RAD21 cleavage may be a general regulatory mechanism for rapid alteration of cellular chromosome conformation and cohesin-dependent transcription regulation. Latent infection with Kasposi’s Sarcoma (KS)-Associated Herpesivirus (KSHV) is linked to malignant transformation of the host cell. KSHV associated pleural effusion lymphomas (PEL) are highly sensitive to endoplasmic reticulum (ER) stress due to underlying defects in ER stress response pathways. We show here that ER stress inducers lead to a rapid activation of KSHV lytic transcripts, and that an underlying mechanism is found in the caspase and calpain-dependent proteolytic cleavage of RAD21. RAD21 is a subunit of the cohesin complex that maintains a chromosome conformation that restricts KSHV lytic cycle transcription. ER stress-induced cleavage of RAD21 alters the KSHV chromosome conformation associated with latency, and a locus-specific increase in RNA polymerase II association and activation. These findings provide new insights into the regulation of KSHV latency and its response to ER stress, and may further the development of selective treatments for KSHV associated PEL and related malignancies.
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