Group VIA phospholipase A2 (iPLA2{beta}) modulates Bcl-x 5′ splice site selection and suppresses anti-apoptotic Bcl-x(L) in {beta}-cells [Lipids]

March 11th, 2015 by Barbour, S. E., Nguyen, P. T., Park, M., Emani, B., Lei, X., Kambalapalli, M., Shultz, J. C., Wijesinghe, D., Chalfant, C. E., Ramanadham, S.

Diabetes is a consequence of reduced β-cell function and mass, due to β-cell apoptosis. ER stress is induced during β-cell apoptosis due to various stimuli and our work indicates that iPLA2β participates in this process. Delineation of underlying mechanism(s) reveals that ER stress reduces antiapoptotic Bcl-x(L) protein in INS-1 cells. The Bcl-x pre-mRNA undergoes alternative pre-mRNA splicing to generate Bcl-x(L) or Bcl-x(s) mature mRNA. We show that both thapsigargin-induced and spontaneous ER stress are associated with reductions in the ratio of Bcl-x(L)/Bcl-x(s) mRNA in INS-1 and islet β-cells. However, chemical inactivation or knockdown of iPLA2β augments the Bcl-x(L)/Bcl-x(s) ratio. Further, the ratio is lower in islets from RIP-iPLA2β-Tg mice, while islets from global iPLA2β-/- mice exhibit the opposite phenotype. In view of our earlier reports that iPLA2β induces ceramide accumulation through neutral sphingo-myelinase 2 and that ceramides shift Bcl-x 5′ splice site (5′SS) selection in favor of Bcl-x(s), we investigated the potential link between Bcl-x splicing and the iPLA2β/ceramide axis. Exogenous C6-ceramide did not alter Bcl-x 5′SS selection in INS-1 cells and NSMase2 inactivation only partially prevented the ER stress-induced shift in Bcl-x splicing. In contrast, 5(S)-HETE augmented the ratio of Bcl-x(L)/Bcl-x(s) by 15.5-fold. Taken together, these data indicate that β-cell apoptosis is, in part, attributable to modulation of 5′ SS selection in the Bcl-x pre-mRNA by bioactive lipids modulated by iPLA2β.
  • Posted in Journal of Biological Chemistry, Publications
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