Xin Shuyu, Du Shujuan, Liu Lingzhi, Xie Yan, Zuo Lielian, Yang Jing, Hu Jingjin, Yue Wenxing, Zhang Jing, Cao Pengfei, Zhu Fanxiu, Lu Jianhong
NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital, Central South University, Changsha, China.
Department of Medical Microbiology, School of Basic Medical Science, Central South University, Changsha, China.
Front Microbiol. 2019 Dec 13;10:2879. doi: 10.3389/fmicb.2019.02879. eCollection 2019.
Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)-mediated DNA episomal genome replication and persistence are essential for the viral pathogenesis. Cyclophilin A (CYPA) is upregulated in EBV-associated nasopharyngeal carcinoma (NPC) with unknown roles. In the present approach, cytosolic CYPA was found to be bound with EBNA1 into the nucleus. The amino acid 376-459 of the EBNA1 domain was important for the binding. CYPA depletion attenuated and ectopic CYPA expression improved EBNA1 expression in EBV-positive cells. The loss of viral copy number was also accelerated by CYPA consumption in daughter cells during culture passages. Mechanistically, CYPA mediated the connection of EBNA1 with oriP (origin of EBV DNA replication) and subsequent oriP transcription, which is a key step for the initiation of EBV genome replication. Moreover, CYPA overexpression markedly antagonized the connection of EBNA1 to Ubiquitin-specific protease 7 (USP7), which is a strong host barrier with a role of inhibiting EBV genome replication. The PPIase activity of CYPA was required for the promotion of oriP transcription and antagonism with USP7. The results revealed a strategy that EBV recruited a host factor to counteract the host defense, thus facilitating its own latent genome replication. This study provides a new insight into EBV pathogenesis and potential virus-targeted therapeutics in EBV-associated NPC, in which CYPA is upregulated at all stages.
爱泼斯坦-巴尔病毒（EBV）核抗原1（EBNA1）介导的DNA游离型基因组复制和维持对于病毒发病机制至关重要。亲环素A（CYPA）在EBV相关鼻咽癌（NPC）中上调，但其作用尚不清楚。在本研究中，发现胞质CYPA与EBNA1结合进入细胞核。EBNA1结构域的氨基酸376 - 459对于这种结合很重要。CYPA缺失会减弱EBV阳性细胞中EBNA1的表达，而异位表达CYPA则会增强其表达。在培养传代过程中，CYPA的消耗也加速了子代细胞中病毒拷贝数的丢失。从机制上讲，CYPA介导了EBNA1与oriP（EBV DNA复制起点）的连接以及随后的oriP转录，这是EBV基因组复制起始的关键步骤。此外，CYPA过表达显著拮抗EBNA1与泛素特异性蛋白酶7（USP7）的连接，USP7是一种强大的宿主屏障，具有抑制EBV基因组复制的作用。CYPA的肽脯氨酰顺反异构酶（PPIase）活性对于促进oriP转录和拮抗USP7是必需的。结果揭示了一种策略，即EBV招募一种宿主因子来对抗宿主防御，从而促进其自身潜伏基因组的复制。本研究为EBV发病机制以及EBV相关NPC中潜在的病毒靶向治疗提供了新的见解，其中CYPA在所有阶段均上调。
