Abstract
It is known that endoplasmic reticulum (ER) and nucleus communicate with each other to cope with ER stress. However, the mechanisms through which extracellular transmission of ER stress occurs remain unexplored. When the ER stress-induced unfolded protein response (UPR) is activated, the X-box binding protein 1 (XBP1) mRNA is spliced by inositol-requiring enzyme-1α (IRE1α) to produce the spliced form of XBP1 (sXBP1). In the present study, we found that sXBP1 mRNA in the cell may be incorporated into the exosomes and was released extracellularly. We found that the ratio of the mRNA levels of sXBP1 to unspliced XBP1 (uXBP1) in the exosome was higher than that of cells in MIN6 mouse pancreatic β cells. A similar effect was observed when XBP1 splicing was induced by overexpressing IRE1α in HEK293T cells. These results suggest that the incorporation of sXBP1 into the exosomes is a novel mechanism of UPR transmitted to extracellularly, which would be triggered when cells are exposed to stress.
Highlights
Cells encounter various environmental stress stimuli, which perturb the functioning of endoplasmic reticulum (ER)
We performed RT-PCR analysis with specific primers for X-box binding protein 1 (XBP1), and found that spliced form of XBP1 (sXBP1) as well as unspliced XBP1 (uXBP1) were expressed in the exosomes (Figure 1C, right band of the panel)
We found that XBP1 and sXBP1 mRNAs were both expressed in the exosomes
Summary
Cells encounter various environmental stress stimuli, which perturb the functioning of endoplasmic reticulum (ER) Such stimuli cause accumulation of unfolded proteins in the ER, which in turn induces the cells to activate the unfolded protein response (UPR) to cope with such a stress (ER stress) (Walter and Ron, 2011). Three major types of UPR stress transducer proteins have been identified: inositol-requiring enzyme-1 (IRE1), double stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6) (Ron and Walter, 2007). Activation of these stress transducer proteins conveys the stress signals to the nucleus. We hypothesized that the ER stress signals may be transduced and packed into the exosomes
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