The JAK-STAT transcriptional regulator, STAT-5, activates the ATM DNA damage pathway to induce HPV 31 genome amplification upon epithelial differentiation.
The JAK-STAT transcriptional regulator, STAT-5, activates the ATM DNA damage pathway to induce HPV 31 genome amplification upon epithelial differentiation.
复制标题
DOI：
10.1371/journal.ppat.1003295
复制
发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Laimins LA
中科院分区：
文献类型：
--
作者：
Hong S;Laimins LA
高危人乳头瘤病毒（HPV）必须逃避先天免疫监视，以建立持续感染和扩增病毒基因组分化。JAK-STAT家族的成员是先天免疫反应的重要调节因子，HPV蛋白下调STAT-1的表达以允许病毒发作的稳定维持。STAT-5是该通路的另一个成员，它调节炎症反应，在控制细胞因子和生长因子对细胞周期的反应中起重要作用。我们的研究表明，HPV E7激活STAT-5磷酸化而不改变总蛋白水平。pimozide药物抑制STAT-5磷酸化可消除分化角化细胞中病毒基因组扩增和晚期基因表达。相比之下，未分化细胞的治疗稳定维持发作没有影响病毒复制。敲除研究表明STAT-5β亚型主要负责这种活性，并且这是通过ATM DNA损伤反应介导的。作为STAT-5的下游靶点，过氧化物酶体增殖体激活受体γ (PPARγ)对ATM通路的成员起作用。总的来说，这些发现确定了一个重要的新的调节机制，先天免疫调节剂STAT-5通过激活ATM DNA损伤反应来促进HPV病毒复制。超过120种类型的人乳头瘤病毒（HPV）已被确定，其中约三分之一感染生殖器粘膜上皮细胞。HPV类型的一个子集是宫颈癌和其他肛门生殖器癌的病原体。HPV的感染生命周期依赖于宿主上皮细胞的分化，病毒基因组扩增和病毒粒子的产生仅限于分化的基底上细胞。当正常的角质形成细胞在分化后退出细胞周期时，hpv阳性的基底上细胞能够重新进入s期来介导生产性复制。HPV在分化细胞中诱导atm依赖的DNA损伤反应，这是病毒基因组扩增所必需的。我们的研究描述了人乳头瘤病毒激活JAK/STAT先天免疫信号通路成员诱导ATM DNA损伤通路的重要机制。这对于依赖分化的高产病毒复制是必要的。hpv必须抑制JAK/STAT通路的一个成员STAT-1的转录，同时激活STAT-5来调节基底上细胞的基因组扩增。E7蛋白激活STAT-5，通过PPARγ途径诱导ATM磷酸化。我们的研究确定了先天免疫信号，ATM DNA损伤途径和生产性HPV复制之间的重要联系，这可能导致HPV诱导感染治疗方法开发的新靶点的表征。
High-risk human papillomavirus (HPV) must evade innate immune surveillance to establish persistent infections and to amplify viral genomes upon differentiation. Members of the JAK-STAT family are important regulators of the innate immune response and HPV proteins downregulate expression of STAT-1 to allow for stable maintenance of viral episomes. STAT-5 is another member of this pathway that modulates the inflammatory response and plays an important role in controlling cell cycle progression in response to cytokines and growth factors. Our studies show that HPV E7 activates STAT-5 phosphorylation without altering total protein levels. Inhibition of STAT-5 phosphorylation by the drug pimozide abolishes viral genome amplification and late gene expression in differentiating keratinocytes. In contrast, treatment of undifferentiated cells that stably maintain episomes has no effect on viral replication. Knockdown studies show that the STAT-5β isoform is mainly responsible for this activity and that this is mediated through the ATM DNA damage response. A downstream target of STAT-5, the peroxisome proliferator-activated receptor γ (PPARγ) contributes to the effects on members of the ATM pathway. Overall, these findings identify an important new regulatory mechanism by which the innate immune regulator, STAT-5, promotes HPV viral replication through activation of the ATM DNA damage response. Over 120 types of human papillomavirus (HPV) have been identified, and approximately one-third of these infect epithelial cells of the genital mucosa. A subset of HPV types are the causative agents of cervical and other anogenital cancers. The infectious life cycle of HPV is dependent on differentiation of the host epithelial cell, with viral genome amplification and virion production restricted to differentiated suprabasal cells. While normal keratinocytes exit the cell cycle upon differentiation, HPV-positive suprabasal cells are able to re-enter S-phase to mediate productive replication. HPV induces an ATM-dependent DNA damage response in differentiating cells that is essential for viral genome amplification. Our studies describe an important mechanism by which human papillomaviruses activate a member of the JAK/STAT innate immune signaling pathway to induce the ATM DNA damage pathway. This is necessary for differentiation-dependent productive viral replication. HPVs must suppress the transcription of one member of the JAK/STAT pathway, STAT-1, while at the same time activating STAT-5 to regulate genome amplification in suprabasal cells. The E7 protein activates STAT-5 leading to induction of ATM phosphorylation through the PPARγ pathway. Our study identifies important links between innate immune signaling, the ATM DNA damage pathway and productive HPV replication that may lead to the characterization of new targets for the development of therapeutics to treat HPV-induced infections.
登录
查看更多内容
影响因子：
4.8
作者：
Heath, C;Cross, NCP
通讯作者：
Cross, NCP
影响因子：
5.4
作者：
Fradet-Turcotte, Amelie;Bergeron-Labrecque, Fanny;Archambault, Jacques
通讯作者：
Archambault, Jacques
影响因子：
5.4
作者：
Juffroy, Olivier;Bugault, Florence;Chakrabarti, Lisa A.
通讯作者：
Chakrabarti, Lisa A.
DOI：
10.1016/j.bbrc.2011.02.052
发表时间：
2011-03-18
影响因子：
3.1
作者：
Kim, Soyeon;Lee, Jae-Jung;Heo, Dae Seog
通讯作者：
Heo, Dae Seog
影响因子：
4.8
作者：
Conger, KL;Liu, JS;Wang, TSF
通讯作者：
Wang, TSF