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

PLoS Pathogens

Moon-Chang Baek¹  Jarrod A. Marto¹  Alison J. Lin²  Yasmine M. Ndassa-Colday³  Laurie A. Silva³  Martha Simpson-Holley³  Wan Jin Jahng³  David M. Knipe³  Sofia Hamirally³  Jeremy P. Kamil³  Sarah Noton³  Donald M. Coen³  David E. Golan⁴ 

[1] Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America;Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America;Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America;Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts, United States of America

关键词: Lamins;    Phosphorylation;    Human cytomegalovirus;    Immunoprecipitation;    Viral replication;    Cell staining;    Nuclear staining;    Protein kinases;   

DOI  :  10.1371/journal.ppat.1000275

学科分类：生物科学（综合）

来源: Public Library of Science

【 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 (Ser22). 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 Ser22 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.

【 授权许可】

CC BY