A ubiquitin-specific protease possesses a decisive role for adenovirus replication and oncogene-mediated transformation.
A ubiquitin-specific protease possesses a decisive role for adenovirus replication and oncogene-mediated transformation.
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DOI：
10.1371/journal.ppat.1003273
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发表时间：
2013-03
期刊：
影响因子：
6.7
通讯作者：
Dobner T
中科院分区：
文献类型：
--
作者：
Ching W;Koyuncu E;Singh S;Arbelo-Roman C;Hartl B;Kremmer E;Speiseder T;Meier C;Dobner T
腺病毒的复制依赖于病毒和细胞蛋白。然而，对促进腺病毒复制的细胞蛋白知之甚少。在我们鉴定这些蛋白质的筛选中，我们发现泛素蛋白酶体途径的一个细胞成分与腺病毒复制的中央调节因子相互作用。我们的结合分析定位了病毒E1B-55K和去泛素酶USP7的N-末端结构域之间的特异性相互作用。RNA干扰介导的USP7下调严重降低了E1B-55K蛋白水平，但更重要的是对腺病毒复制产生了负面影响。我们还成功地重新合成了一种USP7的抑制剂，与敲除背景一样，它减少了腺病毒的复制。进一步的分析表明，不仅腺病毒的生长，以至腺病毒癌基因驱动的细胞转化都依赖于USP7的功能。我们的数据提供了对腺病毒侵占的复杂机制途径的见解，以促进其复制和致癌功能，同时为新的抗病毒策略开辟了可能性。腺病毒感染可导致严重后果，导致死亡，特别是在接受免疫抑制治疗的儿童中。不幸的是，目前还没有特效腺病毒治疗方法来治疗播散性腺病毒感染。我们已经开始确定促进腺病毒生长的宿主因素，并可以确定对腺病毒感染至关重要的细胞蛋白泛素特异性蛋白酶7(USP7)。在这里，我们显示USP7与病毒蛋白E1B-55K相互作用，E1B-55K是腺病毒复制和腺病毒癌基因介导的细胞转化的中央调节因子。我们证明，USP7确保了腺病毒蛋白在感染早期和晚期的稳定和/或适当的表达水平。与此一致的是，USP7的小分子抑制剂显示出有效地降低衣壳蛋白水平和病毒后代数量。因此，在播散性腺病毒感染的情况下，抑制USP7可能是一个有用的治疗选择。此外，我们还能够证明，腺病毒癌基因介导的细胞转化可以受到USP7干扰的阻碍。综上所述，这项研究表明，两种不同的腺病毒疾病机制可以通过靶向一个宿主细胞因子来抑制。
Adenoviral replication depends on viral as well as cellular proteins. However, little is known about cellular proteins promoting adenoviral replication. In our screens to identify such proteins, we discovered a cellular component of the ubiquitin proteasome pathway interacting with the central regulator of adenoviral replication. Our binding assays mapped a specific interaction between the N-terminal domains of both viral E1B-55K and USP7, a deubiquitinating enzyme. RNA interference-mediated downregulation of USP7 severely reduced E1B-55K protein levels, but more importantly negatively affected adenoviral replication. We also succeeded in resynthesizing an inhibitor of USP7, which like the knockdown background reduced adenoviral replication. Further assays revealed that not only adenoviral growth, but also adenoviral oncogene-driven cellular transformation relies on the functions of USP7. Our data provide insights into an intricate mechanistic pathway usurped by an adenovirus to promote its replication and oncogenic functions, and at the same time open up possibilities for new antiviral strategies. Adenoviral infections can result in severe outcomes leading to mortality especially in children undergoing immunosuppressive therapies. Unfortunately, no specific anti-adenoviral treatments are available to treat disseminated adenoviral infections. We have set out to identify host factors promoting adenoviral growth and could identify the cellular protein Ubiquitin-specific protease 7 (USP7) being central to adenoviral infection. Here we show that USP7 interacts with the viral protein E1B-55K, a central regulator of adenoviral replication and adenoviral oncogene-mediated cellular transformation. We demonstrate that USP7 ensures stability and/or proper expression levels of adenoviral proteins at early and late time points of infection. Consistent with this, small-molecule inhibitors of USP7 showed efficient reduction of capsid protein levels and viral progeny numbers. Thus, USP7 inhibition might be a useful treatment option in the context of disseminated adenoviral infections. Moreover, we were also able to show that adenoviral oncogene-mediated cellular transformation can be hampered by USP7 disruption. In summary, this study shows that two different adenoviral disease mechanisms can be inhibited by targeting one host cellular factor.
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影响因子：
3.7
作者：
Banning C;Votteler J;Hoffmann D;Koppensteiner H;Warmer M;Reimer R;Kirchhoff F;Schubert U;Hauber J;Schindler M
通讯作者：
Schindler M
影响因子：
5.4
作者：
Evans, JD;Hearing, P
通讯作者：
Hearing, P
DOI：
10.2105/ajph.45.7.915
发表时间：
1955-07-01
期刊：
AMERICAN JOURNAL OF PUBLIC HEALTH AND THE NATIONS HEALTH
影响因子：
--
作者：
Ginsberg, Harold S.;Gold, Eli;Dingle, John H.
通讯作者：
Dingle, John H.
影响因子：
16
作者：
Faesen, Alex C.;Dirac, Annette M. G.;Sixma, Titia K.
通讯作者：
Sixma, Titia K.
影响因子：
6.2
作者：
Edelmann MJ;Nicholson B;Kessler BM
通讯作者：
Kessler BM