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. 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. © 2013 rodrigues et al.