Dugbe virus ovarian tumour domain interferes with ubiquitin/ISG15-regulated innate immune cell signalling.
Dugbe virus ovarian tumour domain interferes with ubiquitin/ISG15-regulated innate immune cell signalling.
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DOI：
10.1099/vir.0.048322-0
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发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Baron MD
中科院分区：
文献类型：
--
作者：
Bakshi S;Holzer B;Bridgen A;McMullan G;Quinn DG;Baron MD
已显示内罗病毒L蛋白的卵巢肿瘤（OTU）结构域从宿主细胞蛋白中去除泛素和干扰素刺激的基因15蛋白（ISG 15），预期其对细胞信号传导途径具有多种影响。我们已经证实，来自非致病性内罗病毒Dugbe病毒的L蛋白的OTU结构域具有去泛素化和去ISG化活性，并且显示当在细胞中表达时，即使在低剂量下，其也高度有效地阻断TNF-α/NF-κB和干扰素/JAK/STAT信号传导途径。OTU催化位点的点突变[C40 A、H151 A和双突变体]都消除了OTU结构域去泛素化和去ISGylate蛋白的能力，并大大降低了其对细胞信号传导途径的影响，证实了正是这种酶活性负责阻断两种信号传导途径。失活突变体的高水平表达仍然可以阻断信号传导，这表明即使病毒OTU在其催化位点发生突变，病毒OTU仍然可以与其底物结合。内罗病毒L蛋白是一种非常大的蛋白质，通常局限于病毒复制的细胞质中。当OTU结构域通过表达为病毒L蛋白N-末端205 kDa的一部分而被阻止进入细胞核时，它继续阻断I型干扰素信号传导，但不再阻断TNF-α诱导的NF-κB活化。
The ovarian tumour (OTU) domain of the nairovirus L protein has been shown to remove ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host cell proteins, which is expected to have multiple effects on cell signalling pathways. We have confirmed that the OTU domain from the L protein of the apathogenic nairovirus Dugbe virus has deubiquitinating and deISGylating activity and shown that, when expressed in cells, it is highly effective at blocking the TNF-α/NF-κB and interferon/JAK/STAT signalling pathways even at low doses. Point mutations of the catalytic site of the OTU [C40A, H151A and a double mutant] both abolished the ability of the OTU domain to deubiquitinate and deISGylate proteins and greatly reduced its effect on cell signalling pathways, confirming that it is this enzymic activity that is responsible for blocking the two signalling pathways. Expression of the inactive mutants at high levels could still block signalling, suggesting that the viral OTU can still bind to its substrate even when mutated at its catalytic site. The nairovirus L protein is a very large protein that is normally confined to the cytoplasm, where the virus replicates. When the OTU domain was prevented from entering the nucleus by expressing it as part of the N-terminal 205 kDa of the viral L protein, it continued to block type I interferon signalling, but no longer blocked the TNF-α-induced activation of NF-κB.
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影响因子：
3.7
作者：
Bridgen, A;Dalrymple, DA;Elliott, RM
通讯作者：
Elliott, RM
影响因子：
3.8
作者：
DAVIDWES.TS;PORTERFI.JS
通讯作者：
PORTERFI.JS
DOI：
10.1073/pnas.1013388108
发表时间：
2011-02-08
影响因子：
11.1
作者：
James, Terrence W.;Frias-Staheli, Natalia;Mark, Brian L.
通讯作者：
Mark, Brian L.
DOI：
10.1016/j.bbadis.2010.02.006
发表时间：
2010-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Jeon YJ;Yoo HM;Chung CH
通讯作者：
Chung CH
影响因子：
4.8
作者：
Malakhov, MP;Kim, KI;Zhang, DE
通讯作者：
Zhang, DE