Viral Mimicry of Cdc2/Cyclin-Dependent Kinase 1 Mediates Disruption of Nuclear Lamina during Human Cytomegalovirus Nuclear Egress

被引:176
作者
Hamirally, Sofia [1 ]
Kamil, Jeremy P. [1 ]
Ndassa-Colday, Yasmine M. [1 ,2 ]
Lin, Alison J. [1 ,3 ]
Jahng, Wan Jin [1 ]
Baek, Moon-Chang [1 ]
Noton, Sarah [1 ]
Silva, Laurie A. [1 ]
Simpson-Holley, Martha [4 ]
Knipe, David M. [3 ]
Golan, David E. [1 ,5 ]
Marto, Jarrod A. [1 ,2 ]
Coen, Donald M. [1 ]
机构
[1] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA
[5] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA
关键词
UL97; PROTEIN-KINASE; PHOSPHORYLATION SITES; RETINOBLASTOMA PROTEIN; MUTATIONAL ANALYSIS; VIRUS; INFECTION; IDENTIFICATION; REPLICATION; MEMBRANE; PHASE;
D O I
10.1371/journal.ppat.1000275
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The nuclear lamina is a major obstacle encountered by herpesvirus nucleocapsids in their passage from the nucleus to the cytoplasm (nuclear egress). We found that the human cytomegalovirus (HCMV)-encoded protein kinase UL97, which is required for efficient nuclear egress, phosphorylates the nuclear lamina component lamin A/C in vitro on sites targeted by Cdc2/cyclin-dependent kinase 1, the enzyme that is responsible for breaking down the nuclear lamina during mitosis. Quantitative mass spectrometry analyses, comparing lamin A/C isolated from cells infected with viruses either expressing or lacking UL97 activity, revealed UL97-dependent phosphorylation of lamin A/C on the serine at residue 22 (Ser 22). Transient treatment of HCMV-infected cells with maribavir, an inhibitor of UL97 kinase activity, reduced lamin A/C phosphorylation by approximately 50%, consistent with UL97 directly phosphorylating lamin A/C during HCMV replication. Phosphorylation of lamin A/C during viral replication was accompanied by changes in the shape of the nucleus, as well as thinning, invaginations, and discrete breaks in the nuclear lamina, all of which required UL97 activity. As Ser 22 is a phosphorylation site of particularly strong relevance for lamin A/C disassembly, our data support a model wherein viral mimicry of a mitotic host cell kinase activity promotes nuclear egress while accommodating viral arrest of the cell cycle.
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页数:12
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共 59 条
[1]  
ALBRECHT T, 1980, LAB INVEST, V42, P1
[2]   Structural changes in human cytomegalovirus cytoplasmic assembly sites in the absence of UL97 kinase activity [J].
Azzeh, Maysa ;
Honigman, Alik ;
Taraboulos, Albert ;
Rouvinski, Alexander ;
Wolf, Dana G. .
VIROLOGY, 2006, 354 (01) :69-79
[3]   Specific phosphorylation of exogenous protein and peptide substrates by the human cytomegalovirus UL97 protein kinase - Importance of the P+5 position [J].
Baek, MC ;
Krosky, PM ;
He, ZW ;
Coen, DM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (33) :29593-29599
[4]   Large-scale characterization of HeLa cell nuclear phosphoproteins [J].
Beausoleil, SA ;
Jedrychowski, M ;
Schwartz, D ;
Elias, JE ;
Villén, J ;
Li, JX ;
Cohn, MA ;
Cantley, LC ;
Gygi, SP .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (33) :12130-12135
[5]   A probability-based approach for high-throughput protein phosphorylation analysis and site localization [J].
Beausoleil, Sean A. ;
Villen, Judit ;
Gerber, Scott A. ;
Rush, John ;
Gygi, Steven P. .
NATURE BIOTECHNOLOGY, 2006, 24 (10) :1285-1292
[6]   Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action [J].
Biron, KK ;
Harvey, RJ ;
Chamberlain, SC ;
Good, SS ;
Smith, AA ;
Davis, MG ;
Talarico, CL ;
Miller, WH ;
Ferris, R ;
Dornsife, RE ;
Stanat, SC ;
Drach, JC ;
Townsend, LB ;
Koszalka, GW .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2002, 46 (08) :2365-2372
[7]   Human cytomegalovirus inhibits cellular DNA synthesis and arrests productively infected cells in late G1 [J].
Bresnahan, WA ;
Boldogh, I ;
Thompson, EA ;
Albrecht, T .
VIROLOGY, 1996, 224 (01) :150-160
[8]   Comprehensive mutational analysis of a herpesvirus gene in the viral genome context reveals a region essential for virus replication [J].
Bubeck, A ;
Wagner, M ;
Ruzsics, Z ;
Lötzerich, M ;
Iglesias, M ;
Singh, IR ;
Koszinowski, UH .
JOURNAL OF VIROLOGY, 2004, 78 (15) :8026-8035
[9]   Remodelling of the nuclear lamina during human cytomegalovirus infection: role of the viral proteins pUL50 and pUL53 [J].
Camozzi, Daria ;
Pignatelli, Sara ;
Valvo, Cecilia ;
Lattanzi, Giovanna ;
Capanni, Cristina ;
Dal Monte, Paola ;
Landini, Maria Paola .
JOURNAL OF GENERAL VIROLOGY, 2008, 89 :731-740
[10]   Isobaric tags for relative and absolute quantitation (iTRAQ) reproducibility: Implication of multiple injections [J].
Chong, PK ;
Gan, CS ;
Pham, TK ;
Wright, PC .
JOURNAL OF PROTEOME RESEARCH, 2006, 5 (05) :1232-1240