Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.
Biotechnology Institute Thurgau at the University of Konstanz, Kreuzlingen, Switzerland.
Cell Death Dis. 2022 Dec 1;13(12):1015. doi: 10.1038/s41419-022-05461-w.
Valosin-containing protein (VCP)/p97 has emerged as a central regulator of the ubiquitin-proteasome system by connecting ubiquitylation and degradation. The development of CB-5083, an ATPase D2-domain-selective and orally bioavailable inhibitor of VCP/p97, allows targeting of the ubiquitin-proteasome system in human diseases. In this study, we evaluated the effect of CB-5083 on the immune response in mice by using the lymphocytic choriomeningitis virus (LCMV) as an infection model. We demonstrate that LCMV infection increased the susceptibility to CB-5083 treatment in a CD8-independent manner. Administration of CB-5083 to mice reduced the cytotoxic T cell response and impaired viral clearance. Compared to uninfected cells, CB-5083 treatment enhanced the unfolded protein response in LCMV-infected cells. Administration of CB-5083 during the expansion of CD8 T cells led to strong toxicity in mice within hours, which resulted in enhanced IL-6 levels in the serum and accumulation of poly-ubiquitinated proteins. Furthermore, we linked the observed toxicity to the specific formation of aggregates in the skeletal muscle tissue and the upregulation of both lactate dehydrogenase and creatine kinase in the serum.
伏隔核蛋白（VCP）/ p97 通过连接泛素化和降解，成为泛素-蛋白酶体系统的核心调节剂。VCP/p97 的 ATPase D2 结构域选择性和口服生物利用抑制剂 CB-5083 的开发，使得针对人类疾病的泛素-蛋白酶体系统成为可能。在这项研究中，我们使用淋巴细胞性脉络丛脑膜炎病毒（LCMV）作为感染模型，评估了 CB-5083 对小鼠免疫反应的影响。我们证明，LCMV 感染以 CD8 细胞非依赖性的方式增加了对 CB-5083 治疗的敏感性。给予 CB-5083 可降低细胞毒性 T 细胞反应并损害病毒清除。与未感染的细胞相比，CB-5083 处理增强了 LCMV 感染细胞中的未折叠蛋白反应。在 CD8 T 细胞扩增期间给予 CB-5083，会在数小时内导致小鼠产生强烈毒性，导致血清中白细胞介素 6（IL-6）水平升高和多聚泛素化蛋白积累。此外，我们将观察到的毒性与骨骼肌组织中特定聚集体的形成以及血清中乳酸脱氢酶和肌酸激酶的上调联系起来。
