Inhibitory targeting of HHV-8 vIL-6-related interactions.

描述（由申请人提供）：人疱疹病毒8型（HHV-8）是白细胞介素-6（vIL-6）的一种同系物，与HHV-8相关的卡波西肉瘤、原发性渗出性淋巴瘤（PEL）和多中心Castleman病（MCD）的发生和进展有关。我们已经确定，在PEL细胞中，vIL-6在潜伏期期间以低但功能性水平表达; vIL-6在这种情况下支持细胞生长和存活，并且这些功能 主要由位于内质网（ER）中的vIL-6在细胞内介导。因此，vIL-6的胞内、严格自分泌信号可能是一个重要的促进因素， PEL疾病，并代表了疾病发病机制中细胞因子活性的独特模式。vIL-6在PEL细胞中的这种活性的机制尚不清楚，但我们已经确定了vIL-6与一种新蛋白质，维生素K环氧化物还原酶复合物亚单位1变体-2（VKORC 1v2）的功能重要的相互作用，最近还确定了IL-6信号转导蛋白gp130对PEL细胞的持续生长是必不可少的。此外，我们还鉴定了VKORC1v2与硫氧还蛋白还原酶样蛋白1（TMX1）、蛋白质二硫键异构酶A6/P5（PDI-A6）和组织蛋白酶D（catD）的相互作用，这表明VKORC1v2可能具有与vIL-6折叠相关的功能和/或vIL-6通过VKORC1v2相互作用对ER应激反应或catD加工以及促增殖和凋亡信号的相关调节的影响。在本R21申请中，我们建议鉴定和检测vIL-6：VKORC 1v2相互作用和功能性vIL-6：gp130复合的PEL抑制肽和小分子抑制剂;我们还将评估经验证的抑制剂对VKORC 1v2与其新鉴定的细胞相互作用伴侣相互作用预测的功能的影响。因此，这项工作扩展了我们在PEL背景下vIL-6与VKORC1v2和gp130相互作用的功能表征，并提出了靶向这些生物学上重要的病毒-宿主相互作用的分子策略。该项目对未来开发基于药物的治疗方法具有重要意义，这些治疗方法可能与vIL-6可能发挥关键作用的其他HHV-8相关恶性肿瘤有关。

DESCRIPTION (provided by applicant): Human herpesvirus 8 (HHV-8) specifies a homologue of interleukin-6, vIL-6, which is implicated in the development and progression of HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). We have determined that in PEL cells vIL-6 is expressed at low but functional levels during latency; vIL-6 in this setting supports cell growth and survival, and these functions are mediated predominantly intracellularly by vIL-6 localized in the endoplasmic reticulum (ER). Thus, intracrine, strictly autocrine signaling by vIL-6 is likely to be an important contributor to PEL disease and represents a unique mode of cytokine activity in disease pathogenesis. The mechanisms underlying this activity of vIL-6 in PEL cells is not understood, but we have identified a functionally important interaction of vIL-6 with a novel protein, vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2), and also have recently determined that the IL-6 signal transducer, gp130, is essential for sustained growth of PEL cells. Additionally, we have identified interactions of VKORC1v2 with thioredoxin reductase-like protein 1 (TMX1), protein disulfide isomerase A6/P5 (PDI-A6) and cathepsin D (catD) that suggest possible functions of VKORC1v2 related to vIL-6 folding and/or influence of vIL-6, via VKORC1v2 interaction, on ER stress responses or on catD processing and associated regulation of pro-proliferative and apoptotic signaling. In this R21 application, we propose to identify and test in respect of PEL inhibition peptide and small molecule inhibitors of vIL- 6:VKORC1v2 interaction and functional vIL-6:gp130 complexing; we will also assess the effects of validated inhibitors on functions predicted from interaction of VKORC1v2 with its newly identified cellular interaction partners. The work therefore extends our functional characterization of vIL-6 interactions with VKORC1v2 and gp130 in the context of PEL and addresses molecular strategies to target these biologically important virus- host interactions. The project has substantial significance to the future development of drug-based therapies for this and possibly other HHV-8-associated malignancies in which vIL-6 is likely to play a critical role.