To be or not to be phosphorylated : understanding the role of Ebola virus nucleoprotein in the dynamic interplay with the transcriptional activator VP30 and the host phosphatase PP2A-B56
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Taylor and Francis
Abstract
Ebola virus (EBOV) transcription is essentially regulated via dynamic dephosphorylation of its viral transcription activator
VP30 by the host phosphatase PP2A. The nucleoprotein NP has emerged as a third key player in the regulation of this
process by recruiting both the regulatory subunit B56 of PP2A and its substrate VP30 to initiate VP30
dephosphorylation and hence viral transcription. Both binding sites are located in close proximity to each other in NP’s
C-terminal-disordered region. This study investigates NP’s role in VP30 dephosphorylation and transcription activation,
focussing on the spatial requirements of NP’s binding sites. Increasing the distance between PP2A-B56 and VP30 at the
NP interface revealed that close spatial and orientational contact is necessary for efficient VP30 dephosphorylation and
viral transcription. Longer distances were lethal for recombinant EBOV except when a compensatory mutation, NP-
T603I, occurred. This mutation, located between the NP binding sites for PP2A-B56 and VP30, fully restored
functionality. Mass spectrometry showed that T603 is phosphorylated in recEBOV-NPwt virions. Mutational analysis
indicated that T603I facilitates VP30 dephosphorylation in otherwise lethal recEBOV and that dynamic phosphorylation
of NP-T603 is important for efficient primary viral transcription in the WT context. These findings emphasize the critical
and evolutionarily pressured interplay between VP30 and PP2A-B56 within the NP C-terminal-disordered region and
highlight the important role of NP on the regulation of viral transcription during the EBOV life cycle.
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