Adenovirus exploits the cellular aggresome response to accelerate inactivation of the MRN complex
Adenovirus exploits the cellular aggresome response to accelerate inactivation of the MRN complex
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DOI：
10.1128/jvi.79.22.14004-14016.2005
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发表时间：
2005-11-01
影响因子：
5.4
通讯作者：
Berk, AJ
中科院分区：
文献类型：
--
作者：
Liu, Y;Shevchenko, A;Berk, AJ
本文报道的结果表明，腺病毒5利用细胞侵袭体反应来加速MREII-Rad50-NBSI(MRN)复合体的失活，否则会抑制病毒DNA的复制和包装。聚合体是细胞质内的包涵体，见于许多退行性疾病中，由依赖动力蛋白的微管逆行运输到微管组织中心的聚集蛋白形成。病毒E1B-55K蛋白形成侵袭体，在转化细胞和转染E1B-55K表达载体的细胞中隔离P53和MRN。在腺病毒感染过程中，病毒蛋白E4orf3在MRN与E1B-55K结合之前结合在早幼粒细胞白血病蛋白核体中。在腺病毒感染的细胞中，除了E1B-55K外，还需要E4orf3或E4orf6来形成E1B-55K侵袭体，并将Mre11输出到侵袭体。Aggresome的形成有助于保护病毒DNA免受MRN活性的影响，它将MRN隔离在细胞质中，并在其被E1B-55K/E4orf6/Longin BC/Cullin5/Rbx1泛素连接酶泛素化后极大地加速其被蛋白小体降解。我们的结果表明，侵袭者通过泛素-蛋白小体系统显著加速了蛋白质的降解。观察到正常细胞蛋白通过与侵袭体诱导蛋白结合而被隔离到侵袭体时被灭活，这一观察结果暗示了侵袭体样包涵体在退行性疾病中的潜在细胞毒性。
Results reported here indicate that adenovirus 5 exploits the cellular aggresome response to accelerate inactivation of MREII-RAD50-NBSI (MRN) complexes that otherwise inhibit viral DNA replication and packaging. Aggresomes are cytoplasmic inclusion bodies, observed in many degenerative diseases, that are formed from aggregated proteins by dynein-dependent retrograde transport on microtubules to the microtubule organizing center. Viral E1B-55K protein forms aggresomes that sequester p53 and MRN in transformed cells and in cells transfected with an E1B-55K expression vector. During adenovirus infection, the viral protein E4orf3 associates with MRN in promyelocytic leukemia protein nuclear bodies before MRN is bound by E1B-55K. Either E4orf3 or E4orf6 is required in addition to E1B-55K for E1B-55K aggresome formation and MRE11 export to aggresomes in adenovirus-infected cells. Aggresome formation contributes to the protection of viral DNA from MRN activity by sequestering MRN in the cytoplasm and greatly accelerating its degradation by proteosomes following its ubiquitination by the E1B-55K/E4orf6/elongin BC/Cullin5/Rbxl ubiquitin ligase. Our results show that aggresomes significantly accelerate protein degradation by the ubiquitin-proteosome system. The observation that a normal cellular protein is inactivated when sequestered into an aggresome through association with an aggresome-inducing protein has implications for the potential cytotoxicity of aggresome-like inclusion bodies in degenerative diseases.