Stabilization of Myc through Heterotypic Poly-Ubiquitination by mLANA Is Critical for γ-Herpesvirus Lymphoproliferation

PLoS Pathogens

Kenneth M. Kaye¹  J. Pedro Simas²  Lénia Rodrigues²  Nikita Popov³ 

[1] Channing Laboratory and Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America;Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal;Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany

关键词: B cells;    Phosphorylation;    DNA transcription;    Cell cycle;    cell division;    Immunoblotting;    Ubiquitination;    293T cells;    Immunoprecipitation;   

DOI  :  10.1371/journal.ppat.1003554

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Host colonization by lymphotropic γ-herpesviruses depends critically on expansion of viral genomes in germinal center (GC) B-cells. Myc is essential for the formation and maintenance of GCs. Yet, the role of Myc in the pathogenesis of γ-herpesviruses is still largely unknown. In this study, Myc was shown to be essential for the lymphotropic γ-herpesvirus MuHV-4 biology as infected cells exhibited increased expression of Myc signature genes and the virus was unable to expand in Myc defficient GC B-cells. We describe a novel strategy of a viral protein activating Myc through increased protein stability resulting in increased progression through the cell cycle. This is acomplished by modulating a physiological post-translational regulatory pathway of Myc. The molecular mechanism involves Myc heterotypic poly-ubiquitination mediated via the viral E3 ubiquitin-ligase mLANA protein. EC5SmLANA modulates cellular control of Myc turnover by antagonizing SCFFbw7 mediated proteasomal degradation of Myc, mimicking SCFβ-TrCP. The findings here reported reveal that modulation of Myc is essential for γ-herpesvirus persistent infection, establishing a link between virus induced lymphoproliferation and disease.

【 授权许可】

CC BY