The PERK pathway influences the scale of XBP1-mediated gene expression and cell fate in response to ER stress via miR-30c-2*.

No abstract

SUMMARY Cellular disturbances that cause accumulation of misfolded proteins in the endoplasmic reticulum (ER) lead to a condition referred to as “ER stress” and trigger the unfolded protein response (UPR), a signaling pathway that attempts to restore ER homeostasis. The complexity of UPR signaling can generate adaptive and apoptotic outputs, depending on the nature and duration of the ER stress. MicroRNAs (miRNAs), small non-coding RNAs that typically repress gene expression, have recently emerged as key gene regulators of the pro-adaptive/pro-apoptotic molecular switch emanating from the ER. Importantly, select miRNAs have been shown to directly regulate key UPR components.

Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a signaling mechanism that allows cellular adaptation to ER stress by engaging pro-adaptive transcription factors and alleviating protein folding demand. One such transcription factor, X-box binding protein (XBP1), originates from the inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1) UPR stress sensor. XBP1 up-regulates a pool of genes involved in ER protein translocation, protein folding, vesicular trafficking and ER- associated protein degradation. Recent data suggest that the regulation of XBP1 expression and transcriptional activity may be a tissue- and stress-dependent phenomenon. Moreover, the intricacies involved in “fine-tuning” XBP1 activity in various settings are now coming to light. Here, we provide an overview of recent developments in understanding the regulatory mechanisms underlying XBP1 expression and activity and discuss the significance of these new insights.

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.