Kaposi’s Sarcoma-Associated Herpesvirus Induces Nrf2 during De Novo Infection of Endothelial Cells to Create a Microenvironment Conducive to Infection. (PLOS Pathogens 2014, 10(10):e1004460)

報告日期: 2015/03/17
報告時間: 16:00/16:50
報告學生: 鄭怡琳(以英文報告)
講評老師: 陳舜華

Kaposi’s Sarcoma-Associated Herpesvirus Induces Nrf2 during De Novo Infection of Endothelial Cells to Create a Microenvironment Conducive to Infection

Gjyshi, O., et al.

PLoS Pathog. 10: e1004460 (2014).

Student: Yi-Lin Cheng (鄭怡琳)                            Time: 16:00~16:50, Mar. 17, 2015

Commentator:Dr.Shun-Hua Chen (陳舜華博士)     Place: Room 602


        Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of hyper-proliferative disorders such as Kaposi’s sarcoma (KS) and primary effusion B-cell lymphoma. The life cycle of KSHV alternates between lytic and latent phases. During de novo infection, KSHV first binds to the receptors followed by triggering downstream signaling for viral entry, macropinocytosis, gene expression, or establishment of latency [1]. Several studies showed that reactive oxygen species (ROS) not only plays the critical roles in KSHV lytic reactivation in latently-infected endothelial cells, but also in establishment of KSHV infection during de novo infection [2]. However, these studies did not explore the downstream effects of ROS activation. One of the downstream targets of ROS is nuclear factor E2-related factor 2 (Nrf2), which is a transcription factor involved in the transcription of hundreds of genes [3]. It can be activated by several kinds of virus infection. In this study, the authors demonstrated that Nrf2 induction, manipulated by ROS, was essential for KSHV de novo infection by regulating the transcriptional activation of several viral and host genes. First, they found that the level of Nrf2 was increased in KS lesions. Consistently, KSHV induced both phosphorylated and total Nrf2 in human umbilical vein endothelial cells. After treatment with the inhibitors of ROS and the Nrf2-activating kinases, the stability, phosphorylation and transcriptional activity of Nrf2 were all inhibited. Furthermore, several well-known target genes of Nrf2 and other novel genes, such as VEGF and COX-2, that induced by KSHV were abolished after knockdown of Nrf2. In addition, the COX-2 product PGE2 induced Nrf2 activity, creating the feed-forward loop between Nrf2 and COX-2. Overexpression of KSHV latent gene ORF71 enhanced the Nrf2 protein and target genes expression. They also identified activated Nrf2 colocalized with the KSHV genome and the latency protein LANA-1. Finally, Nrf2 knockdown reduced the lytic gene, ORF50, but increased the latent gene, ORF73. Taken together, these results demonstrate that during de novo infection, KSHV develops multiple mechanisms to activate Nrf2, which plays important roles in manipulating multiple host and viral genes to create a microenvironment conducive to KSHV infection.


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  3. Nguyen T., et al. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J. Biol. Chem. 284: 13291–13295 (2009).