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J Biol Chem. 2019 Aug 1. pii: jbc.RA119.009601. doi: 10.1074/jbc.RA119.009601. [Epub ahead of print]

Casein kinase-2 mediated phosphorylation increases the SUMO-dependent activity of the cytomegalovirus transactivator IE2.

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National Centre for Biological Sciences, India.


Many viral factors manipulate the host post-translational modification (PTM) machinery for efficient viral replication. In particular, phosphorylation and SUMOylation can distinctly regulate the activity of the human cytomegalovirus (HCMV) transactivator immediate early 2 (IE2). However, the molecular mechanism of this process is unknown. Using various structural, biochemical, and cell-based approaches, here we uncovered that IE2 exploits a cross-talk between phosphorylation and SUMOylation. A scan for SUMO-interacting motifs (SIMs) revealed two SIMs in IE2, and a real-time SUMOylation assay indicated that the N-terminal SIM (IE2-SIM1) enhances IE2 SUMOylation up to 4-fold. Kinetic analysis and structural studies disclosed that IE2 is a SUMO cis-E3 ligase. We also found that two putative casein kinase 2 (CK2) sites adjacent to IE2-SIM1 are phosphorylated in-vitro and in cells. The phosphorylation drastically increased IE2-SUMO affinity, IE2 SUMOylation, and cis-E3 activity of IE2. Additional salt bridges between the phosphoserines and SUMO accounted for the increased IE2-SUMO affinity. Phosphorylation also enhances the SUMO-dependent transactivation activity and auto-repression activity of IE2. Together, our findings highlight a novel mechanism whereby SUMOylation and phosphorylation of the viral cis-E3 ligase and transactivator protein IE2 works in tandem to enable transcriptional regulation of viral gene.


SUMO-interacting motif (SIM); enzyme kinetics; host-pathogen interaction; nuclear magnetic resonance (NMR); phosphorylation; post-translational modification (PTM); sumoylation; transcription coactivator; viral protein; viral transcription

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