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"Histone deacetylase 6 links autophagy induction with reactivation of Kaposiís sarcoma-associated herpesvirus from latency"

Hyejin Shin
Interdisciplinary Biomedical Sciences Program
M.S. 2009, Sungkyunkwan University, Seoul, Korea
B.S. 2007, Sungkyunkwan University, Seoul, Korea

Thesis Advisor: David Lukac, Ph.D.
Associate Professor
Department of Microbiology, Biochemistry and Molecular Genetics

Monday, January 4, 2016
1:00 P.M., ICPH 1st floor auditorium


Kaposiís sarcoma-associated herpesvirus (KSHV) is implicated in the etiology of the cancers Kaposiís sarcoma (KS) and primary effusion lymphoma (PEL). Reactivation of KSHV from latency is necessary for progression of these diseases. Histone deacetylase inhibitors (HDACis) reactivate latent KSHV and dramatically remodel the viral genome topology and chromatin architecture. We found that class I HDACis were sufficient to reactivate the virus but differed in potency. Valproic acid (VPA) was the most effective HDACi while trichostatin A (TSA) induced less widespread lytic gene expression. VPA was only slightly superior to TSA in inducing histone acetylation of Rtaís promoter, but only VPA induced significant production of infectious virus, suggesting that HDAC regulation after Rta expression has a dramatic effect on reactivation progression. Tubacin, a specific inhibitor of HDAC6, also inhibited VPA-stimulated reactivation. Our data showed that inhibition of HDAC classes I and IIa and maintenance of HDAC6 (IIb) activity are required for optimal KSHV reactivation.
Since HDAC6 is a central regulator of autophagy in the cell cytoplasm, our work suggested that autophagy might have a pro-viral role during KSHV reactivation. Our preliminary data suggested that HDAC6 supports KSHV reactivation by stimulating autophagy and/or an unknown nuclear process, downstream of Rta expression. We determined that VPA treatment of infected B cells is sufficient to induce initiation of autophagy. The number of autophagosomes increased during reactivation progression. Tubacin reduced autophagosome formation, providing additional support for a pro-viral role for autophagy in reactivation. Autophagic flux is also induced during reactivation and is a general requirement for successful KSHV reactivation. Our data thus suggest that the entire autophagy pathway is involved in KSHV reactivation. We also found that inhibiting autophagic flux reduced expression of the viral lytic switch protein Rta. Finally, ectopic HDAC6 cooperates with Rta to induce production of mature infectious virus in Vero cells in a mechanism that seems to require nuclear/cytoplasmic shuttling. We suggest that HDAC6 and autophagy regulate reactivation by post-translationally enhancing Rta expression and function. Overall, our data provide evidence that HDAC6 links autophagy to KSHV reactivation.

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