Caspase-1 promotes Epstein-Barr virus replication by targeting the large tegument protein deneddylase to the nucleus of productively infected cells.
Caspase-1 promotes Epstein-Barr virus replication by targeting the large tegument protein deneddylase to the nucleus of productively infected cells.
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caspase-1通过将大的tegument蛋白质deneddydylase靶向有效感染细胞的细胞核来促进爱泼斯坦 - 巴尔病毒的复制。
DOI：
10.1371/journal.ppat.1003664
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Masucci MG
中科院分区：
文献类型：
--
作者：
Gastaldello S;Chen X;Callegari S;Masucci MG
疱疹病毒的大被膜蛋白含有N-末端半胱氨酸蛋白酶，其具有有效的泛素和NEDD 8特异性解偶联酶活性，但这些酶在病毒复制过程中的功能在很大程度上仍然未知。作为模型BPLF 1，由EB病毒（EBV）编码的同源物，我们发现，生产性病毒周期的诱导不影响泛素结合的总水平，但伴随着BPLF 1依赖性的NEDD 8-加合物的减少和游离NEDD 8的积累。BPLF 1的表达促进cullin降解和细胞核中cullin-RING连接酶（CRL）底物的稳定，而细胞质CRL及其底物不受影响。CAND 1的N-末端可逆转核CRL的失活，从而抑制BPLF 1与cullin的结合并阻止病毒DNA的有效复制。脱乙酰基酶活性靶向细胞核依赖于胱天蛋白酶-1对催化N-末端的加工。半胱天冬酶-1的抑制严重损害病毒DNA的合成和感染性病毒的释放，指出了以前未被认识到的作用，细胞反应的危险信号触发的EBV再活化，促进病毒复制。病毒依赖于宿主细胞进行复制，并已进化出复杂的策略来操纵和利用细胞代谢途径和防御反应。更好地了解这些病毒策略将为抗病毒治疗提供新的靶点。疱疹病毒的大被膜蛋白的N-末端编码泛素和NEDD 8特异性解偶联酶，但该酶在病毒复制过程中的功能在很大程度上是未知的。在这里，我们报告说，内源性表达的BPLF 1，同源编码的EB病毒（EBV），促进了显着减少NEDD 8共轭物和积累的游离NEDD 8细胞进入生产性病毒周期。BPLF 1在细胞核中发挥其去核酶活性，促进有效病毒复制所需的cullin-RING连接酶（CRL）底物的积累。病毒酶靶向细胞核依赖于caspase-1对催化N-末端的加工。半胱天冬酶-1的抑制严重损害病毒DNA的合成和感染性病毒的释放，这表明细胞对EBV再活化引发的危险信号的反应在促进病毒复制中具有意想不到的作用。
The large tegument proteins of herpesviruses contain N-terminal cysteine proteases with potent ubiquitin and NEDD8-specific deconjugase activities, but the function of the enzymes during virus replication remains largely unknown. Using as model BPLF1, the homologue encoded by Epstein-Barr virus (EBV), we found that induction of the productive virus cycle does not affect the total level of ubiquitin-conjugation but is accompanied by a BPLF1-dependent decrease of NEDD8-adducts and accumulation of free NEDD8. Expression of BPLF1 promotes cullin degradation and the stabilization of cullin-RING ligases (CRLs) substrates in the nucleus, while cytoplasmic CRLs and their substrates are not affected. The inactivation of nuclear CRLs is reversed by the N-terminus of CAND1, which inhibits the binding of BPLF1 to cullins and prevents efficient viral DNA replication. Targeting of the deneddylase activity to the nucleus is dependent on processing of the catalytic N-terminus by caspase-1. Inhibition of caspase-1 severely impairs viral DNA synthesis and the release of infectious virus, pointing a previously unrecognized role of the cellular response to danger signals triggered by EBV reactivation in promoting virus replication. Viruses rely on the host cell for replication and have evolved sophisticated strategies to manipulate and harness the cellular metabolic pathways and defense responses. A better knowledge of these viral strategies will provide new targets for antiviral therapies. The N-terminus of the large tegument proteins of herpesviruses encodes an ubiquitin and NEDD8-specific deconjugase, but the function of the enzyme during virus replication is largely unknown. Here we report that, endogenously expressed BPLF1, the homolog encoded by Epstein-Barr virus (EBV), promotes a dramatic decrease of NEDD8-conjugates and the accumulation of free NEDD8 in cells entering the productive virus cycle. BPLF1 exerts its deneddylase activity in the nucleus, which promotes the accumulation of cullin-RING ligase (CRL) substrates that are required for efficient virus replication. Targeting of the viral enzyme to the nucleus is dependent on processing of the catalytic N-terminus by caspase-1. Inhibition of caspase-1 severely impairs viral DNA synthesis and the release of infectious virus, pointing to an unexpected role of the cellular response to danger signals triggered by EBV reactivation in promoting virus replication.
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影响因子：
64.5
作者：
Duda, David M.;Borg, Laura A.;Scott, Daniel C.;Hunt, Harold W.;Hammel, Michal;Schulman, Brenda A.
通讯作者：
Schulman, Brenda A.
影响因子：
3.7
作者：
Bheda A;Yue W;Gullapalli A;Whitehurst C;Liu R;Pagano JS;Shackelford J
通讯作者：
Shackelford J
影响因子：
5.4
作者：
Guerreiro-Cacais, Andre Ortlieb;Uzunel, Mehmet;Levitsky, Victor
通讯作者：
Levitsky, Victor
影响因子：
64.5
作者：
Gurcel, Laure;Abrami, Laurence;van der Goot, F. Gisou
通讯作者：
van der Goot, F. Gisou
DOI：
10.1073/pnas.0706295104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Jarosinski, Keith;Kattenhorn, Lisa;Osterrieder, Nikolaus
通讯作者：
Osterrieder, Nikolaus