Study On The Function Of IRF4 And RIK In ? Herpesvirus-Associated Lymphomas

? herpesviruses include Kaposi's sarcoma-associated herpesvirus(KSHV),Epstein-Barr virus(EBV)and murine gammaherpesvirus 68(MHV68).? herpesvirus is associated with lymphoproliferative disorders and the development of various cancers.? herpesvirus mainly maintains a latent state in associated lymphoma cells.The current study mainly focuses on the role of IRF4 and unknown gene RIK in ? herpesvirus-associated lymphomagenesis.On the one hand,we found that IRF4 regulates EBV reactivation in Burkitt's lymphoma(BL)cells;on the other hand,we screened MHV68 latently infected B lymphoma cells and identified an unknown gene with high expression,named as Rik.We performed the prelimary analysis of RIK function.In the first part of this paper,we focus on the role of IRF4 in EBV reactivation in BL cell lines.EBV can establish latency in memory B cells,whereas the differentiation toward plasma cell is associated with the induction of EBV lytic cycle in latently infected B cells.EBV lytic cycle is mainly triggered and reg?lated by the two immediate-early switch proteins Zta and RTA.Previous study showed that XBP-1 and Bimp-1,plasma cell transcription factors,could trigger EBV lytic reactivation by directly activating Zta or RTA transcription.Here we show that another plasma cell transcription factor,interferon reg?latory factor 4(IRF4)can activate EBV Zta and RTA promoters but is not able to directly active EBV lytic gen expression in latently infected Burkitt's lymphoma cells.IRF4 is either not expressed or expressed at a low level in EBV positive BL cells.Endogenous IRF4 expression is detectable in Raji cell.IRF4 knockout in Raji cell suppresses EBV lytic gene expression induced by anti-Ig,consistently accompanied by Blimp-1 expression reduction.Overexpression of Blimp1 can rescue Zta and Ead expression in IRF4 knockout C-2 Raji cells.Our res?lts indicate that IRF4 can promote EBV lytic gen expression in BL cells and IRF4 reg?lation of EBV reactivation involves the reg?lation of Blimp-1 expression.In the second part,we screened MHV68 latently infected B lymphoma cell line and identified a gene with high expression,which was named as Rik.This gene function is unknown.In our prelimary functional study,we found that Rik plays a role in cell survival.We observed that cell survival rate was lower in Rik knockout(KO)MEF cells under starvation;meanwhile,the activation of caspase-3 and caspase-8 was increased in Rik KO MEF cells,indicating that Rik KO induces caspase-3 and caspase-8 activation and promotes cell death.From the analysis of Rik interacting proteins in mass spectrometry assay,we found that Rik may interact with a pro-survival protein,HAX-1.We verified the interaction and determined the region of Rik that interacts with HAX-1.The role of Rik in cell survival and death,whether through the interaction with HAX-1,remains to be further studied.