B cell expression of E3 ubiquitin ligase Cul4b promotes chronic gammaherpesvirus infection in vivo.

The gammaherpesviruses, including human Epstein-Barr virus, human Kaposi's sarcoma-associated herpesvirus, and murine gammaherpesvirus 68 (MHV68, γHV68, MuHV-4), are ubiquitous pathogens that directly contribute to the genesis of a wide variety of malignancies, including B cell lymphomas. In vivo, these viruses infect naïve B cells and then usurp B cell signaling pathways to drive infected cells, independent of antigen stimulation, through germinal center (GC) reactions and thereby establish lifelong latency in the memory B cell compartment. However, the specific molecular determinants by which these viruses establish chronic latent infection in B cells in vivo remain largely unknown. The E3 ubiquitin ligase Cullin 4b (Cul4b) is well recognized as a central player in regulating cell proliferation, DNA damage repair, and gene transcription by catalyzing the ubiquitination and degradation of numerous cellular proteins. Here, we determined whether B cell-intrinsic expression of Cul4b is required for chronic gammaherpesvirus infection in vivo. Through MHV68 infection of mice with B cell-specific Cul4b deficiency, we found that loss of Cul4b expression in B cells severely impeded the establishment of latency at peripheral sites. In particular, a lack of Cul4b expression in B cells significantly attenuated the expansion of virus-infected GC B cells, suggesting that gammaherpesviruses may manipulate a previously unknown function of Cul4b in GC B cell biology. Cumulatively, these findings demonstrate that Cul4b promotes chronic gammaherpesvirus infection in vivo. [ABSTRACT FROM AUTHOR]