Tousled-like Kinases Modulate Reactivation of Gammaherpesviruses from Latency

Patrick J. Dillon et al. 2013. Cell Host Microbe.13, 204-214.

Speaker: Li-Jie Kao (高力捷)                 Time: 13:00~14:00, Sep. 25, 2013

Commentator: Dr. Ai-Li Shiau (蕭璦莉 老師)    Place: Room 601

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to gammaherpesvirus and is linked to a number of human malignancies, such as Kaposi’s sarcoma and primary effusion lymphoma. KSHV can establish latency in most infected cells; however, a small portion of latently infected cells can undergo spontaneous lytic replication to release infectious virus. This low level of viral reactivation is believed to be important for persistent infection and malignancies¹. Because the switch between the latent and lytic phases of viral life cycle plays key role in tumorigenesis, it is important to understand. Previous studies have shown that some kinases are involved in KSHV reactivation. To determine the cellular kinases that control KSHV reactivation from latency, the authors performed a small interfering RNA kinome screen and then identified the Tousled-like kinases (TLKs) as cellular kinases involved in KSHV reactivation. There are two mammalian homologs, TLK1 and TLK2. The authors found that knockdown of TLK2 resulted in robust viral reactivation in latent KSHV-infected cells. The authors also found that knockdown of TLK2 caused the increase of KSHV ORF50 promoter activity and led to lytic gene expression and production of infectious virus. A previous study has shown that TLKs can phosphorylate histone H3²and phospho-histone H3 can associate with chromatin and lead to chromatin condensation. To determine whether knockdown of TLK2 can decrease phospho-histone H3 associated with ORF50 promoter, the authors performed chromatin immunoprecipitation assay and found that the amount of phospho-histone H3 associated with ORF50 promoter decreased following TLK2 knockdown and led to KSHV reactivation. The authors also found that TLKs can regulate reactivation of another gammaherpesvirus, Epstein-Barr virus. In conclusion, TLKs can suppress gammaherpesvirusreactivation and promote viral latency.

References

1.      Grundhoff, A., and Ganem, D. Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis. 2004. J. Clin. Invest. 113, 124–136.

2.      Li, Y., DeFatta, R., Anthony, C., Sunavala, G., and De Benedetti, A.

A translationally regulated Tousled kinase phosphorylates histone H3 and confers radioresistance when overexpressed. 2001. Oncogene. 20, 726–738.