Abstract
Viruses interact with the host cellular pathways to optimize cellular conditions for replication. The Human Cytomegalovirus (HCMV) Immediate-Early protein 1 (IE1) is the first viral protein to express during infection. It is a multifunctional and conditionally essential protein for HCMV infection. SUMO signaling regulates several cellular pathways that are also targets of IE1. Consequently, IE1 exploits SUMO signaling to regulate these pathways. The covalent interaction of IE1 and SUMO (IE1-SUMOylation) is well studied. However, the non-covalent interactions between SUMO and IE1 are unknown. We report two SUMO-Interacting Motifs (SIMs) in IE1, one at the end of the core domain and another in the C-terminal domain. NMR titrations showed that IE1-SIMs bind to SUMO1 but not SUMO2. Two critical functions of IE1 are inhibition of SUMOylation of Promyelocytic leukemia protein (PML) and transactivation of viral promoters. Although the non-covalent interaction of IE1 and SUMO is not involved in the inhibition of PML SUMOylation, it contributes to the transactivation activity. The transactivation activity of IE1 was previously correlated to its ability to inhibit PML SUMOylation. Our results suggest that transactivation and inhibition of PML SUMOylation are independent activities of IE1.
Highlights
During the lytic cycle of herpesviruses infection, the Immediate Early (IE) genes are expressed first, followed by early and late viral genes
The binding of predicted Immediate-Early protein 1 (IE1)-SUMO-Interacting Motifs (SIMs) to SUMO was studied by Nuclear Magnetic Resonance (NMR) spectroscopy
The IE1-SIM1 was titrated into 15N isotope-labeled SUMO1, and a series of 15N-edited HSQC were recorded with increasing concentrations of IE1SIM1 (Figure 1B)
Summary
During the lytic cycle of herpesviruses infection, the Immediate Early (IE) genes are expressed first, followed by early and late viral genes. IE genes are multifunctional regulatory proteins that optimize the host cell environment for viral propagation. IE gene products help evade host antiviral responses, modulate the host cell cycle and transcribe viral genes. For Human Cytomegalovirus (HCMV), the two predominant IE proteins are IE1 and IE2, which are produced via alternative splicing of the mRNA from Major Immediate Early Promoter (MIEP) (Thomsen et al, 1984). IE1 can transactivate promoters by a variety of mechanisms. It enhances the expression of various cellcycle proteins like DNA polymerase α, dihydrofolate reductase, or thymidine kinase by inhibiting transcriptional repressor p107 (Poma et al, 1996). IE1 inhibits chromatin-modifying enzymes like HDAC, ATRX, and DAXX to regulate transcription at the epigenetic level
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