The E3 Ubiquitin Ligase FBW7 Is A Key Regulator Of BCL6 And Plays A Critical Role In A Functional Germinal Center Reaction

The transcription inhibitor Bcl6 plays an important role in germinal center(GC)B cell development and functional differentiation.Aberrant control of Bcl6 expression will directly lead to B cell lymphomagenesis.Therefore,the precise control of Bcl6 expression and activity in the germinal center has important significance in both immune physiology and disease pathology.Although many groups have studied Bcl6 transcription regulation,little is known about post-translational regulation of Bcl6 protein.In this study,we have found that an important tumor suppressor,Fbw7,mediates Bcl6 protein degradation by forming SCFFbw7 complex,resulting in regulated Bcl6 protein stability in the cell.In this study,we have forecasted the substrate of Fbw7 by bioinformatics and found that the Bcl6 contains the degradation signal sequence for direct Fbw7 recognition,and this sequence is highly conserved in different species.Then,by a series of biochemistry and molecular biology approaches,we found that both exogenous and endogenous Fbw7 can combine Bcl6 and mediates the ubiquitination and degradation of Bcl6.In addition,we have found that Fbw7-mediated Bcl6 degradation relies on phosphate kinase JNK phosphorylation.Finally,we have explored the physiological significance of Fbw7 mediated Bcl6 degradation.We have generated GC B cell-specific Fbw7 conditional knock-out mice.We found that conditional deletion of Fbw7 in GC B-cells does not affect GC initiation and development.However,the function of GC B-cells including Ig class-switch and memory B-cells development has been altered in Fbw7-deficient GC B-cells.Fbw7-deficient GC B-cells exhibit a severely diminished Ig class-switch,leading to an IgM-dominated antibody response.Interestingly,GC B cell-specific Fbw7 mutant mice exhibit an enhanced memory B-cell response due to an imbalance between Bcl6 and Blimp 1 resulting in a biased differentiation from germinal center B cells to the memory cells.In summary,our study has found that Fbw7-mediated Bcl6 degradation plays an important role in GC reaction and suggested that targeting Fbw7 may provide a new therapeutic approach for the treatment of autoimmune disease and B-cell lymphoma.