Protein arginine methyltransferase 1 regulates herpes simplex virus replication through ICP27 RGG-box methylation.
Protein arginine methylation is involved in viral infection and replication through the modulation of diverse cellular processes including RNA metabolism, cytokine signaling, and subcellular localization. It has been suggested previously that the protein arginine methylation of the RGG-box of ICP27 is required for herpes simplex virus type-1 (HSV-1) viral replication and gene expression in vivo. However, a cellular mediator for this process has not yet been identified. In our current study, we show that the protein arginine methyltransferase 1 (PRMT1) is a cellular mediator of the arginine methylation of ICP27 RGG-box. We generated arginine substitution mutants in this domain and examined which arginine residues are required for methylation by PRMT1. R138, R148 and R150 were found to be the major sites of this methylation but additional arginine residues serving as minor methylation sites are still required to sustain the fully methylated form of ICP27 RGG. We also demonstrate that the nuclear foci-like structure formation, SRPK interactions, and RNA-binding activity of ICP27 are modulated by the arginine methylation of the ICP27 RGG-box. Furthermore, HSV-1 replication is inhibited by hypomethylation of this domain resulting from the use of general PRMT inhibitors or arginine mutations. Our data thus suggest that the PRMT1 plays a key role as a cellular regulator of HSV-1 replication through ICP27 RGG-box methylation.
Yu
Jungeun
J
Department of Microbiology, Chungnam National University, Yuseong-gu, Daejon 305-764, Republic of Korea.
Shin
Bongjin
B
Park
Eui-Soon
ES
Yang
Sujeong
S
Choi
Seunga
S
Kang
Misun
M
Rho
Jaerang
J
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D009154:Mutation; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018139:Simplexvirus / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
D004791:Enzyme Inhibitors; C057120:ICP27 protein, human herpesvirus 1; D017874:Immediate-Early Proteins; D012097:Repressor Proteins; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases