PuSH - Publication Server of Helmholtz Zentrum München: Modulation of alternative splicing during early infection of human primary B lymphocytes with Epstein-Barr virus (EBV): A novel function for the viral EBNA-LP protein.

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Manet, E.* ; Polvèche, H.* ; Mure, F.* ; Mrozek-Gorska, P. ; Roisné-Hamelin, F.* ; Hammerschmidt, W. ; Auboeuf, D.* ; Gruffat, H.*

Modulation of alternative splicing during early infection of human primary B lymphocytes with Epstein-Barr virus (EBV): A novel function for the viral EBNA-LP protein.

Nucleic Acids Res. 49, 10657–10676 (2021)

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Epstein-Barr virus (EBV) is a human herpesvirus associated with human cancers worldwide. Ex vivo, the virus efficiently infects resting human B lymphocytes and induces their continuous proliferation. This process is accompanied by a global reprogramming of cellular gene transcription. However, very little is known on the impact of EBV infection on the regulation of alternative splicing, a pivotal mechanism that plays an essential role in cell fate determination and is often deregulated in cancer. In this study, we have developed a systematic time-resolved analysis of cellular mRNA splice variant expression during EBV infection of resting B lymphocytes. Our results reveal that major modifications of alternative splice variant expression appear as early as day 1 post-infection and suggest that splicing regulation provides-besides transcription-an additional mechanism of gene expression regulation at the onset of B cell activation and proliferation. We also report a role for the viral proteins, EBNA2 and EBNA-LP, in the modulation of specific alternative splicing events and reveal a previously unknown function for EBNA-LP-together with the RBM4 splicing factor-in the alternative splicing regulation of two important modulators of cell proliferation and apoptosis respectively, NUMB and BCL-X.

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