The unfolded protein response, microRNA-214, and expression of the transcription factor XBP1

Abstract

The transcription factor X-box binding protein 1 (XBP1) plays critical roles in the immune system. For example, XBP1 is required for plasma cell development and can disrupt proper function of tumor-associated dendritic cells. A number of post-transcriptional mechanisms regulate XBP1, but a complete understanding of the processes that govern its expression and activity in distinct situations is lacking. The active form of XBP1, termed XBP1s, is dependent upon cytoplasmic splicing of Xbp1 mRNA by IRE1, a transmembrane endoribonuclease/kinase positioned in the endoplasmic reticulum (ER) membrane. IRE1 is a key signal transducer in the cellular response to ER stress, also known as the unfolded protein response (UPR). The IRE1-XBP1 pathway coordinates a broad program of gene transcription that promotes functions of the secretory pathway and alters various aspects of lipid homeostasis under conditions that perturb the ER environment and/or increase demand on its protein folding capacity. ER stress also activates the UPR signal transducer PERK, an ER transmembrane kinase that mediates efficient repression of protein synthesis. Previous studies have shown that microRNA(miR)-214 can negatively regulate XBP1 expression and is down-regulated during ER stress. Using PERK-deficient mouse embryo fibroblasts, we have found that ER stress-mediated diminishment of miR-214 is partially dependent on the PERK pathway, suggesting a novel mechanism of regulatory crosstalk between the PERK and IRE1-XBP1 branches of the UPR. The significance of miR-214 in the cellular response to ER stress and to XBP1-mediated events is under investigation.