Regulation of protein homeostasis by cardiac glycosides
Cardiac glycosides suppress the unfolded protein response
- Date:
- June 7, 2021
- Source:
- Nagoya City University
- Summary:
- The unfolded protein response (UPR) is a pivotal mechanism to mitigate protein homeostasis through transcriptional or translational control. On the other hand, since dysregulation of UPR has been associated with various human diseases, the compounds modulating UPR can clarify the pathological significance of the UPR.
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In the present study, Dr. Hidetoshi Hayashi (Professor, Nagoya City University) and collaborators screened small-molecule compounds that suppress UPR, using Myanmar wild plant extracts library. 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.
They 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, basically used for cardiac insufficiency therapy, 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 the understanding of the pathological or physiological importance of UPR signaling.
Story Source:
Materials provided by Nagoya City University. Note: Content may be edited for style and length.
Journal Reference:
- Muneshige Tokugawa, Yasumichi Inoue, Kan’ichiro Ishiuchi, Chisane Kujirai, Michiyo Matsuno, Masaki Ri, Yuka Itoh, Chiharu Miyajima, Daisuke Morishita, Nobumichi Ohoka, Shinsuke Iida, Hajime Mizukami, Toshiaki Makino, Hidetoshi Hayashi. Periplocin and cardiac glycosides suppress the unfolded protein response. Scientific Reports, 2021; 11 (1) DOI: 10.1038/s41598-021-89074-x
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