Abstract
The unfolded protein response (UPR) controls protein homeostasis through transcriptional and translational regulation. However, dysregulated UPR signaling has been associated with the pathogenesis of many human diseases. Therefore, the compounds modulating UPR may provide molecular insights for these pathologies in the context of UPR. Here, we screened small-molecule compounds that suppress UPR, using a library of Myanmar wild plant extracts. The screening system to track X-box binding protein 1 (XBP1) splicing activity revealed that the ethanol extract of the Periploca calophylla stem inhibited the inositol-requiring enzyme 1 (IRE1)-XBP1 pathway. We isolated and identified periplocin as a potent inhibitor of the IRE1-XBP1 axis. Periplocin also suppressed other UPR axes, protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Examining the structure–activity relationship of periplocin revealed that cardiac glycosides also inhibited UPR. Moreover, periplocin suppressed the constitutive activation of XBP1 and exerted cytotoxic effects in the human multiple myeloma cell lines, AMO1 and RPMI8226. These results reveal a novel suppressive effect of periplocin or the other cardiac glycosides on UPR regulation, suggesting that these compounds will contribute to our understanding of the pathological or physiological importance of UPR.
Highlights
The pathological activation of UPR may provide the molecular basis for therapy for these d iseases[8]
IRE1 is activated by endoplasmic reticulum (ER) stress through autophosphorylation, which results in the splicing out of 26 specific nucleotides from X-box binding protein 1 (XBP1) mRNA10
We found that the ethanol extract of P. calophylla stem suppressed XBP1 splicing induced by the ER stressors, tunicamycin (TM) and thapsigargin (TG) (Fig. 1b and Supplementary Fig. S2)
Summary
The pathological activation of UPR may provide the molecular basis for therapy for these d iseases[8]. The present results demonstrated that the ethanol extract of the Periploca calophylla stem (P. calophylla EtOH ex.) inhibited the activation of X-box binding protein 1 (XBP1) splicing in a screening assay using HEK293 cells that express the luciferase reporter gene fused with the XBP1 splicing region. Through activity-guided fractionation and subsequent structural analysis, p eriplocin[9] was isolated as an active compound from the methanol extract of the P. calophylla stem. In an analysis of the structure–activity relationship, various cardiac glycosides, including periplocin, suppressed XBP1 splicing. The results of the present study indicate the potential of periplocin and other cardiac glycosides as molecular candidates for novel inhibitors of the global UPR pathway
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