Byrd et al. describe how a microRNA (miRNA) fine-tunes a cell's response to ER stress.
When stressful conditions disrupt the ER's normal function, the cell activates an unfolded protein response (UPR) that restores the organelle's ability to fold and export proteins to the secretory pathway. The transcription factor XBP1 is a key component of the UPR that boosts ER capacity and cell survival by upregulating factors such as molecular chaperones and vesicle transport proteins. XBP1 itself is regulated by alternative UPR-mediated splicing of its mRNA, but Byrd et al. wondered whether expression of the transcription factor might also be controlled by miRNAs.
The researchers identified an miRNA called miR-30c-2* that targets the 3′-untranslated region of the XBP1 mRNA. miR-30c-2* was induced in cells subjected to ER stress. Its upregulation depended on the protein kinase PERK (another key component of the UPR), which drove miR-30c-2* production by activating the transcription factor NF-κB. Overexpressing miR-30c-2* reduced the levels of XBP1 and its target genes in stressed cells, whereas blocking miR-30c-2* activity had the opposite effect, boosting XBP1 levels and promoting cell survival.
Senior author Joseph Brewer thinks that miR-30c-2* helps prevent XBP1 from becoming overly active during the UPR. In some cases, it may be better for stressed cells to die instead of struggling to adapt to limited ER function. Brewer now wants to investigate whether NF-κB also regulates miR-30c-2* and XBP1 downstream of other signals, such as the pathways that upregulate B cells’ secretory capacity when they differentiate into plasma cells.