Microtubule depolymerization activates the Epstein-Barr virus lytic cycle through protein kinase C pathways in nasopharyngeal carcinoma cells.
Elevated levels of antibodies against Epstein-Barr virus (EBV) and the presence of viral DNA in plasma are reliable biomarkers for the diagnosis of nasopharyngeal carcinoma (NPC) in high-prevalence areas, such as South-East Asia. The presence of these viral markers in the circulation suggests that a minimal level of virus reactivation may have occurred in an infected individual, although the underlying mechanism of reactivation remains to be elucidated. Here, we showed that treatment with nocodazole, which provokes the depolymerization of microtubules, induces the expression of two EBV lytic cycle proteins, Zta and EA-D, in EBV-positive NPC cells. This effect was independent of mitotic arrest, as viral reactivation was not abolished in cells synchronized at interphase. Notably, the induction of Zta by nocodazole was mediated by transcriptional upregulation via protein kinase C (PKC). Pre-treatment with inhibitors for PKC or its downstream signalling partners p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) abolished the nocodazole-mediated induction of Zta and EA-D. Interestingly, the effect of nocodazole, as well as colchicine and vinblastine, on lytic gene expression occurred only in NPC epithelial cells but not in cells derived from lymphocytes. These results establish a novel role of microtubule integrity in controlling the EBV life cycle through PKC and its downstream pathways, which represents a tissue-specific mechanism for controlling the life-cycle switch of EBV.
Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan.|Graduate Program of Biotechnology in Medicine of National Tsing Hua University and National Health Research Institutes, National Tsing Hua University, Hsinchu 300, Taiwan.
Yi-Ru
YR
Liu
National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan.|Graduate Program of Biotechnology in Medicine of National Tsing Hua University and National Health Research Institutes, National Tsing Hua University, Hsinchu 300, Taiwan.
Sheng-Yen
SY
Huang
National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan.
Jen-Yang
JY
Chen
Department of Medical Science, National Tsing Hua University, Hsinchu 300, Taiwan.|Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300, Taiwan.
Lily Hui-Ching
LH
Wang
D002277:Carcinoma; D002460:Cell Line; D004789:Enzyme Activation; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D058105:Polymerization; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015739:Nocodazole