Epstein-Barr virus BGLF4 kinase induces disassembly of the nuclear lamina to facilitate virion production.
DNA viruses adopt various strategies to modulate the cellular environment for efficient genome replication and virion production. Previously, we demonstrated that the BGLF4 kinase of Epstein-Barr virus (EBV) induces premature chromosome condensation through the activation of condensin and topoisomerase IIalpha (C. P. Lee, J. Y. Chen, J. T. Wang, K. Kimura, A. Takemoto, C. C. Lu, and M. R. Chen, J. Virol. 81:5166-5180, 2007). In this study, we show that BGLF4 interacts with lamin A/C and phosphorylates lamin A protein in vitro. Using a green fluorescent protein (GFP)-lamin A system, we found that Ser-22, Ser-390, and Ser-392 of lamin A are important for the BGLF4-induced disassembly of the nuclear lamina and the EBV reactivation-mediated redistribution of nuclear lamin. Virion production and protein levels of two EBV primary envelope proteins, BFRF1 and BFLF2, were reduced significantly by the expression of GFP-lamin A(5A), which has five Ser residues replaced by Ala at amino acids 22, 390, 392, 652, and 657 of lamin A. Our data indicate that BGLF4 kinase phosphorylates lamin A/C to promote the reorganization of the nuclear lamina, which then may facilitate the interaction of BFRF1 and BFLF2s and subsequent virion maturation. UL kinases of alpha- and betaherpesviruses also induce the disassembly of the nuclear lamina through similar sites on lamin A/C, suggesting a conserved mechanism for the nuclear egress of herpesviruses.
Lee
Chung-Pei
CP
Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Huang
Yu-Hao
YH
Lin
Su-Fang
SF
Chang
Yao
Y
Chang
Yu-Hsin
YH
Takada
Kenzo
K
Chen
Mei-Ru
MR
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D046912:Multiprotein Complexes / Q000378:metabolism; D034881:Nuclear Lamina / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D014764:Viral Proteins / Q000502:physiology*; D014771:Virion / Q000502:physiology*; D014775:Virus Activation
D000951:Antigens, Neoplasm; C406064:BFRF1 protein, Human herpesvirus 4; D004268:DNA-Binding Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D014764:Viral Proteins; C108312:condensin complexes; C440308:lamin C; D011494:Protein Kinases; C406063:BGLF4 protein, Epstein-Barr virus; C082380:UL13 protein, Simplexvirus; D017346:Protein Serine-Threonine Kinases; D000251:Adenosine Triphosphatases; D004250:DNA Topoisomerases, Type II