MicroRNA-mediated repression of XBP1: a novel mechanism for regulation of a UPR transcriptional activator (62.15)

Abstract

Abstract The unfolded protein response (UPR), a multi-faceted signaling system emanating from the endoplasmic reticulum (ER) membrane, plays a critical role in the differentiation of B-lymphocytes into antibody-secreting plasma cells. Specifically, XBP1(S), a UPR transcriptional activator generated by IRE1-mediated splicing of Xbp1(u) mRNA, mediates expansion of the ER, up-regulates expression of many secretory pathway genes, and is required for normal antibody production. However, a full understanding of the molecular mechanisms regulating expression of Xbp1 is still lacking. Using bioinformatics analysis, we identified a microRNA (miR-30c-2*) predicted to target Xbp1 mRNA. Indeed, luciferase reporter assays demonstrated that miR-30c-2* targets a site in the 3’-untranslated region of Xbp1 mRNA in a sequence-specific manner. Over-expression of miR-30c-2* attenuated expression of both Xbp1 and XBP1(S) target genes, consistent with diminished expression of XBP1(S) protein. Furthermore, our studies revealed that expression of miR-30c-2* is up-regulated during UPR activation, concomitant with Xbp1, suggesting a feedback mechanism for XBP1(S) homeostasis. Finally, preliminary studies provided evidence linking expression of miR-30c-2* with specific UPR signaling events. These data provide the first link between microRNA and the UPR and, importantly, implicate miR-30c-2* in the regulation of Xbp1 and plasma cell differentiation.