USP7 targeting by HHV-8 vIRFs
HHV-8 vIRF 靶向 USP7
基本信息
- 批准号:10581544
- 负责人:
- 金额:$ 40.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AblationAcquired Immunodeficiency SyndromeAffectApoptosis InhibitorApoptoticAreaB lymphoid malignancyBindingBiologicalBiologyCatalytic DomainCell SurvivalCell physiologyCellsConsensusDataDevelopmentDiseaseEndotheliumEpitheliumEtiologyFutureGenesHerpesviridaeHomologous GeneHuman Herpesvirus 8In VitroInterferonsKaposi SarcomaLinkLymphoma cellLyticLytic PhaseMG132MapsMediatingMethodsModificationMulticentric Angiofollicular Lymphoid HyperplasiaMutateN-terminalNatural ImmunityPathway interactionsPharmaceutical PreparationsPhenotypePolyubiquitinProductivityProteinsPublic HealthPublishingRefractoryRegulationReportingResearchRoleSeminalSignal TransductionStressSubstrate InteractionSystemTRAF DomainTherapeuticTherapeutic AgentsTimeTransfectionUbiquitinUbiquitinationVariantViralViral ProteinsVirusVirus DiseasesVirus LatencyVirus ReplicationWorkXeroderma Pigmentosumadductantiviral drug developmentcell typecellular targetingdisorder preventiongenetic resistancelatency-associated nuclear antigenlatent infectionlytic replicationmutantnovelprimary effusion lymphomatargeted treatmentubiquitin isopeptidaseubiquitin-specific proteaseviral interferon regulatory factorviral interferon regulatory factor-3
项目摘要
Human herpesvirus 8 (HHV-8) is involved etiologically in AIDS-associated diseases Kaposi’s sarcoma, primary
effusion lymphoma (PEL), and multicentric Castleman’s disease; in all, viral latent and lytic functions are believed
to contribute. HHV-8 encodes four interferon regulatory factor homologues (vIRFs) that can interact in inhibitory
fashion with cellular IRFs and/or a variety of other cellular proteins involved in innate immunity and antiviral
stress signaling. However, very few of these interactions have been detected and assessed functionally in the
context of virus infection. It has recently been reported that both vIRF-1 and vIRF-4 interact with the
deubiquitinase USP7 [ubiquitin-specific protease 7, also called herpesvirus-associated USP (HAUSP)], and we
have identified vIRF-3 (published) and vIRF-2 (new data in this revised application) as additional interaction
partners of USP7. While vIRF-4 interacts with the USP7 N-terminal TRAF domain via a core motif, ASTS,
matching the consensus USP7-interaction motif, A/PxxS, present in many cellular and viral proteins, vIRF-1 and
vIRF-3 have, respectively, a single and duplicated TRAF domain-interacting EGPS core motif and vIRF-2
appears to interact with USP7 in a novel manner. vIRFs 1, 2 and 3 are expressed in latently (in addition to
lytically) infected PEL cells, but in other examined cell types, all vIRFs appear to be expressed only during lytic
replication. Through depletion-based analyses in PEL cells and gene ablation in the context of HHV-8 bacmid
(BAC16) virus-infected iSLK (inducible, epithelial) cells, we have determined that vIRF-1, like vIRF-3, is important
for the viability of latently infected PEL cells and that vIRF-3, in contrast to vIRF-1, negatively regulates HHV-8
productive replication. Furthermore, using WT or USP7-refractory (EGPS motif-mutated) vIRF-1/3 “rescue” of
vIRF depletion phenotypes in PEL cells and BAC16 mutants expressing USP7-refractory variants of vIRFs 1 and
3, we have determined that vIRF-1 and vIRF-3 interactions with USP7 are involved centrally in the respective
latent and lytic activities. USP7 depletion revealed directly the importance of the deubiquitinase for latent PEL
cell viability and HHV-8 productive replication. We have also identified ubiquitin modifications of vIRFs 1 and 3,
raising the possibility of USP7 modulation of vIRF expression and/or activities via ubiquitin editing. In this
application we propose to: (1) examine the functional and biological consequences of vIRF-2 targeting of USP7;
(2) characterize structurally and functionally vIRF ubiquitination and USP7 editing thereof; (3) identify vIRF-
regulated USP7 targets in the context of HHV-8 infected cells and the functional significance of these proteins
in HHV-8 biology. The proposed work will, for the first time, characterize vIRF-2 targeting of USP7 and identify
mechanisms underlying biological activities mediated via vIRF-USP7 interactions, of demonstrated importance
to both latent and lytic HHV-8 biology. The project will provide mechanistic and biological information (at present
sparse) about the significance of viral targeting of USP7 and has the potential to inform future development of
novel antiviral and therapeutic agents directed against the mechanisms and pathways identified by this project.
人类疱疹病毒 8 (HHV-8) 在病因学上涉及艾滋病相关疾病卡波西肉瘤、原发性
渗出性淋巴瘤 (PEL) 和多中心卡斯尔曼病;人们相信病毒具有潜伏和溶解功能;
HHV-8 编码四种可以在抑制中相互作用的干扰素调节因子同源物 (vIRF)。
与细胞 IRF 和/或参与先天免疫和抗病毒的各种其他细胞蛋白的时尚
然而,这些相互作用很少被检测到并在功能上进行评估。
最近有报道称,vIRF-1 和 vIRF-4 均与病毒感染相互作用。
去泛素酶 USP7 [泛素特异性蛋白酶 7,也称为疱疹病毒相关 USP (HAUSP)],我们
已将 vIRF-3(已发布)和 vIRF-2(本修订后的应用程序中的新数据)确定为附加交互
而 vIRF-4 通过核心基序 ASTS 与 USP7 N 末端 TRAF 结构域相互作用,
匹配常见的 USP7 相互作用基序 A/PxxS,存在于许多细胞和病毒蛋白 vIRF-1 和
vIRF-3 分别具有单个和重复的 TRAF 域相互作用 EGPS 核心基序,而 vIRF-2
vIRF 1、2 和 3 似乎以一种新颖的方式与 USP7 相互作用(除了
裂解)感染的 PEL 细胞,但在其他检查的细胞类型中,所有 vIRF 似乎仅在裂解期间表达
通过 PEL 细胞中基于耗竭的分析和 HHV-8 bacmid 背景下的基因消融。
(BAC16) 病毒感染的 iSLK(诱导型上皮细胞)细胞,我们确定 vIRF-1 与 vIRF-3 一样很重要
对于潜伏感染的 PEL 细胞的活力,与 vIRF-1 相比,vIRF-3 负向调节 HHV-8
此外,使用 WT 或 USP7 难治性(EGPS 基序突变)vIRF-1/3“拯救”
PEL 细胞和表达 vIRF 1 和 USP7 难治性变体的 BAC16 突变体中 vIRF 耗尽表型
如图 3 所示,我们确定 vIRF-1 和 vIRF-3 与 USP7 的相互作用集中参与各自的
潜在和裂解活性直接揭示了去泛素酶对潜在 PEL 的重要性。
我们还鉴定了 vIRF 1 和 3 的泛素修饰,
提高了 USP7 通过泛素编辑调节 vIRF 表达和/或活性的可能性。
我们建议的应用是:(1)检查 vIRF-2 靶向 USP7 的功能和生物学后果;
(2)表征vIRF泛素化及其USP7编辑的结构和功能;(3)鉴定vIRF-;
HHV-8 感染细胞中调节的 USP7 靶标以及这些蛋白质的功能意义
在 HHV-8 生物学中,拟议的工作将首次描述 USP7 的 vIRF-2 靶向并确定。
通过 vIRF-USP7 相互作用介导的生物活性机制,具有重要意义
该项目将提供潜伏和裂解 HHV-8 生物学信息(目前)。
稀疏)了解病毒靶向 USP7 的重要性,并有可能为未来的发展提供信息
针对该项目确定的机制和途径的新型抗病毒和治疗药物。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
STAT and Janus kinase targeting by human herpesvirus 8 interferon regulatory factor in the suppression of type-I interferon signaling.
STAT 和 Janus 激酶通过人疱疹病毒 8 干扰素调节因子靶向抑制 I 型干扰素信号传导。
- DOI:
- 发表时间:2022-07
- 期刊:
- 影响因子:6.7
- 作者:Xiang, Qiwang;Yang, Zunlin;Nicholas, John
- 通讯作者:Nicholas, John
Direct and biologically significant interactions of human herpesvirus 8 interferon regulatory factor 1 with STAT3 and Janus kinase TYK2.
人疱疹病毒 8 干扰素调节因子 1 与 STAT3 和 Janus 激酶 TYK2 的直接且具有生物学意义的相互作用。
- DOI:
- 发表时间:2023-11
- 期刊:
- 影响因子:6.7
- 作者:Yang, Zunlin;Xiang, Qiwang;Nicholas, John
- 通讯作者:Nicholas, John
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John Nicholas其他文献
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{{ truncateString('John Nicholas', 18)}}的其他基金
HHV-8 vIRF interactions in the context of infection
HHV-8 vIRF 在感染情况下的相互作用
- 批准号:
9085244 - 财政年份:2015
- 资助金额:
$ 40.94万 - 项目类别:
HHV-8 vIRF interactions in the context of infection
HHV-8 vIRF 在感染情况下的相互作用
- 批准号:
8994365 - 财政年份:2015
- 资助金额:
$ 40.94万 - 项目类别:
Inhibitory targeting of HHV-8 vIL-6-related interactions.
HHV-8 vIL-6 相关相互作用的抑制性靶向。
- 批准号:
8467210 - 财政年份:2013
- 资助金额:
$ 40.94万 - 项目类别:
Inhibitory targeting of HHV-8 vIL-6-related interactions.
HHV-8 vIL-6 相关相互作用的抑制性靶向。
- 批准号:
8595304 - 财政年份:2013
- 资助金额:
$ 40.94万 - 项目类别:
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