Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch.
Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch.
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DOI：
10.7554/elife.06068
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发表时间：
2015-04-07
期刊：
影响因子：
7.7
通讯作者：
Trono D
中科院分区：
文献类型：
--
作者：
Rauwel B;Jang SM;Cassano M;Kapopoulou A;Barde I;Trono D
人巨细胞病毒（HCMV）是一种高度流行的病原体，主要通过在造血干细胞（HSC）中建立潜伏期诱导终身感染。再激活的回合通常由免疫系统控制，但对于免疫受损的个体，如器官移植接受者，可能是致命的。在这里，我们揭示了HCMV在人CD34+ HSC中的潜伏期反映了KAP1（主要的协同抑制因子）与HP1和SETDB1组蛋白甲基转移酶在病毒基因组上的募集，从而导致转录沉默。在裂解感染过程中，KAP1仍然与病毒基因组相关，但其诱导异染色质的活性被mtor介导的磷酸化抑制。相应地，HCMV可以通过KAP1敲低或KAP1磷酸化的药理学诱导而被迫脱离潜伏期，这一过程可以通过TNF-α激活NFkB来增强。这些结果提示了减少巨细胞病毒感染和清除器官移植病毒的新方法。DOI: http://dx.doi.org/10.7554/eLife.06068.001人类巨细胞病毒（HCMV）是一种极其常见的病毒，可导致人类终身感染。大多数人在童年时期接触过HCMV，健康人很少会出现任何疾病症状。然而，在免疫系统较弱的人群中——例如新生儿、艾滋病患者或接受过器官移植的个体——hcmv可能导致危及生命的疾病。免疫系统很难对抗这种感染，因为HCMV能够隐藏在骨髓内被称为造血干细胞的细胞中。在这些细胞内，病毒可以在“休眠”状态下存活多年，然后被重新激活并开始再次繁殖。在大多数人中，免疫系统能够控制HCMV的新爆发，病毒再次进入休眠状态，但在免疫系统较弱的个体中，病毒重新激活更有可能导致严重疾病。先前的研究结果表明，当HCMV感染造血干细胞时，人类蛋白质会关闭许多病毒基因的表达，从而使病毒失活。当被感染的干细胞变成一种叫做树突状细胞的免疫细胞时，这种病毒可以被重新激活，但目前尚不清楚这是如何控制的。在这里，Rauwel等人揭示了一种名为KAP1的人类蛋白质负责关闭干细胞中的病毒基因。它通过与另外两种蛋白质相互作用来改变这些基因中DNA的结构。然而，如果干细胞被刺激变成树突状细胞，KAP1就会变得不活跃，这就允许病毒基因被激活。Rauwel等人也表明，通过药物阻断KAP1的活性，有可能迫使HCMV脱离休眠状态。这可能有助于开发防止病毒在免疫系统较弱的患者中引起严重疾病的治疗方法。例如，它可以在骨髓移植到新个体之前，从骨髓中清除休眠的HCMV感染。DOI: http://dx.doi.org/10.7554/eLife.06068.002
Human cytomegalovirus (HCMV) is a highly prevalent pathogen that induces life-long infections notably through the establishment of latency in hematopoietic stem cells (HSC). Bouts of reactivation are normally controlled by the immune system, but can be fatal in immuno-compromised individuals such as organ transplant recipients. Here, we reveal that HCMV latency in human CD34+ HSC reflects the recruitment on the viral genome of KAP1, a master co-repressor, together with HP1 and the SETDB1 histone methyltransferase, which results in transcriptional silencing. During lytic infection, KAP1 is still associated with the viral genome, but its heterochromatin-inducing activity is suppressed by mTOR-mediated phosphorylation. Correspondingly, HCMV can be forced out of latency by KAP1 knockdown or pharmacological induction of KAP1 phosphorylation, and this process can be potentiated by activating NFkB with TNF-α. These results suggest new approaches both to curtail CMV infection and to purge the virus from organ transplants. DOI: http://dx.doi.org/10.7554/eLife.06068.001 Human cytomegalovirus (HCMV) is an extremely common virus that causes life-long infections in humans. Most individuals are exposed to HCMV during childhood, and the infection rarely causes any symptoms of disease in healthy individuals. However, in people with weaker immune systems—for example, newborn babies, people with AIDS, or individuals who have received an organ transplant—HCMV can cause life-threatening illnesses. It is difficult for the immune system to fight the infection because HCMV is able to hide in cells within the bone marrow called hematopoietic stem cells. Inside these cells, the virus can survive in a ‘dormant’ state for many years, before being reactivated and starting to multiply again. In most people, the immune system manages to control this new outbreak of HCMV, and the virus becomes dormant again, but reactivation of the virus in individuals with weakened immune systems is much more likely to cause serious illness. The results of previous studies suggest that when HCMV infects the hematopoietic stem cells, human proteins switch off the expression of many virus genes, which makes the virus inactive. The virus can be reactivated when infected stem cells change into a type of immune cell called dendritic cells, but it is not clear how this is controlled. Here, Rauwel et al. reveal that a human protein called KAP1 is responsible for switching off the virus genes in the stem cells. It does so by interacting with two other proteins to alter the structure of the DNA in these genes. However, if the stem cells are stimulated to change into dendritic cells, KAP1 becomes inactive, which allows the virus genes to be switched on. Rauwel et al. also show that it is possible to force HCMV out of its dormant state by using drugs to block the activity of KAP1. This may aid the development of treatments that prevent the virus from causing serious illness in patients with weakened immune systems. For example, it could be used to remove dormant HCMV infections from bone marrow before it is transplanted into a new individual. DOI: http://dx.doi.org/10.7554/eLife.06068.002