Stabilization of Myc through heterotypic poly-ubiquitination by mLANA is critical for γ-herpesvirus lymphoproliferation.
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. EC5S(mLANA) modulates cellular control of Myc turnover by antagonizing SCF(Fbw7) mediated proteasomal degradation of Myc, mimicking SCF(β-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.
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Lénia
L
Rodrigues
Nikita
N
Popov
Kenneth M
KM
Kaye
J Pedro
JP
Simas
D000818:Animals; D002460:Cell Line; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D006566:Herpesviridae Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D018144:Rhadinovirus / Q000235:genetics / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C489428:Myc protein, mouse; C581957:Orf73 protein, Murid herpesvirus 4; D016271:Proto-Oncogene Proteins c-myc; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases