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Reactivation of Epstein–Barr virus can be triggered by an Rta protein mutated at the nuclear localization signal

¹ Department of Microbiology, College of Medicine, National Taiwan University, Room 722, Number 1, Section 1, Jen-Ai Road, Taipei, Taiwan
² Center of General Education, National Taipei College of Nursing, Taipei, Taiwan
³ Extramural Research Affairs Department, National Health Research Institute, Taipei, Taiwan

Correspondence
Tsuey-Ying Hsu
tyhsu{at}ha.mc.ntu.edu.tw

Rta, an immediate-early protein of Epstein–Barr virus (EBV), is a transcriptional activator that induces lytic gene expression and triggers virus reactivation. Being located predominantly in the nucleus, Rta can exert its transactivation function through either direct DNA binding or certain indirect mechanisms mediated by cellular signalling and other transcriptional factors. This study examined whether the subcellular localization of Rta was critical for the induction of target genes. First, ⁴¹⁰KRKK⁴¹³ was identified as a nuclear localization signal (NLS) of Rta. An Rta mutant with the NLS converted to ⁴¹⁰AAAA⁴¹³ showed cytoplasmic localization and failed to activate the promoter of BGLF5. Interestingly, ectopic expression of the Rta mutant still disrupted EBV latency in an epithelial cell line. Reporter gene assays revealed that the NLS-mutated Rta retained the ability to activate two lytic promoters, Zp and Rp, at a considerable level. Thus, the cytoplasmic Rta mutant could induce expression of endogenous Zta and Rta, triggering reactivation of EBV.

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