Inhibition of KAP1 enhances hypoxia-induced Kaposi's sarcoma-associated herpesvirus reactivation through RBP-Jk

Liming Zhang, Caixia Zhu, Yi Guo, Fang Wei, Jie Lu, Jing Qin, Shuvomoy Banerjee, Junwen Wang, Hong Shang, Subhash C. Verma, Zhenghong Yuan, Erle S. Robertson, Qiliang Cai

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Hypoxia-inducible factor 1α (HIF-1α) has been frequently implicated in many cancers as well as viral pathogenesis. Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to several human malignancies. It can stabilize HIF-1α during latent infection and undergoes lytic replication in response to hypoxic stress. However, the mechanism by which KSHV controls its latent and lytic life cycle through the deregulation of HIF-1α is not fully understood. Our previous studies showed that the hypoxia-sensitive chromatin remodeler KAP1 was targeted by the KSHV-encoded latency-associated nuclear antigen (LANA) to repress expression of the major lytic replication and transcriptional activator (RTA). Here we further report that an RNA interferencebased knockdown of KAP1 in KSHV-infected primary effusion lymphoma (PEL) cells disrupted viral episome stability and abrogated sub-G1/G1 arrest of the cell cycle while increasing the efficiency of KSHV lytic reactivation by hypoxia or using the chemical 12-O-tetradecanoylphorbol-13-acetate (TPA) or sodium butyrate (NaB). Moreover, KSHV genome-wide screening revealed that four hypoxia-responsive clusters have a high concurrence of both RBP-Jk and HIF-1α binding sites (RBS+HRE) within the same gene promoter and are tightly associated with KAP1. Inhibition of KAP1 greatly enhanced the association of RBP-Jk with the HIF-1α complex for driving RTA expression not only in normoxia but also in hypoxia. These results suggest that both KAP1 and the concurrence of RBS+HRE within the RTA promoter are essential for KSHV latency and hypoxia-induced lytic reactivation.

Original languageEnglish (US)
Pages (from-to)6873-6884
Number of pages12
JournalJournal of virology
Volume88
Issue number12
DOIs
StatePublished - Jun 2014

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Zhang, L., Zhu, C., Guo, Y., Wei, F., Lu, J., Qin, J., Banerjee, S., Wang, J., Shang, H., Verma, S. C., Yuan, Z., Robertson, E. S., & Cai, Q. (2014). Inhibition of KAP1 enhances hypoxia-induced Kaposi's sarcoma-associated herpesvirus reactivation through RBP-Jk. Journal of virology, 88(12), 6873-6884. https://doi.org/10.1128/JVI.00283-14