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KSHV RTA abolishes NF?B responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome.


ABSTRACT: Kaposi's sarcoma herpesvirus (KSHV) is a gamma-2 herpesvirus present in all cases of Kaposi's sarcoma, primary effusion lymphoma (PEL), and some cases of multicentric Castleman's disease. Viral FLICE inhibitory protein (vFLIP) is a latently expressed gene that has been shown to be essential for survival of latently infected PEL cells by activating the NF?B pathway. Inhibitors of either vFLIP expression or the NF?B pathway result in enhanced lytic reactivation and apoptosis. We have observed a decrease in vFLIP protein levels and of NF?B activation in the presence of the KSHV lytic switch protein RTA. Whereas vFLIP alone induced expression of the NF?B responsive genes ICAM1 and TNF?, inclusion of RTA decreased vFLIP induced ICAM1 and TNF? expression in both co-transfected 293T cells and in doxycycline induced TREx BCBL1 cells. RTA expression resulted in proteasome dependent destabilization of vFLIP. Neither RTA ubiquitin E3 ligase domain mutants nor a dominant-negative RAUL mutant abrogated this effect, while RTA truncation mutants did, suggesting that RTA recruits a novel cellular ubiquitin E3 ligase to target vFLIP for proteasomal degradation, allowing for inhibition of NF?B responsive gene expression early during lytic reactivation.

SUBMITTER: Ehrlich ES 

PROVIDER: S-EPMC3948842 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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KSHV RTA abolishes NFκB responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome.

Ehrlich Elana S ES   Chmura Jennifer C JC   Smith John C JC   Kalu Nene N NN   Hayward Gary S GS  

PloS one 20140310 3


Kaposi's sarcoma herpesvirus (KSHV) is a gamma-2 herpesvirus present in all cases of Kaposi's sarcoma, primary effusion lymphoma (PEL), and some cases of multicentric Castleman's disease. Viral FLICE inhibitory protein (vFLIP) is a latently expressed gene that has been shown to be essential for survival of latently infected PEL cells by activating the NFκB pathway. Inhibitors of either vFLIP expression or the NFĸB pathway result in enhanced lytic reactivation and apoptosis. We have observed a de  ...[more]

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