Periplocin and cardiac glycosides suppress the unfolded protein response

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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f4d5583a2ef44886af048e669358049f
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spelling	oai:doaj.org-article:f4d5583a2ef44886af048e669358049f2021-12-02T14:41:55ZPeriplocin and cardiac glycosides suppress the unfolded protein response10.1038/s41598-021-89074-x2045-2322https://doaj.org/article/f4d5583a2ef44886af048e669358049f2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89074-xhttps://doaj.org/toc/2045-2322Abstract 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.Muneshige TokugawaYasumichi InoueKan’ichiro IshiuchiChisane KujiraiMichiyo MatsunoMasaki RiYuka ItohChiharu MiyajimaDaisuke MorishitaNobumichi OhokaShinsuke IidaHajime MizukamiToshiaki MakinoHidetoshi HayashiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
description	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.
format	article
author	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
author_facet	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
author_sort	Muneshige Tokugawa
title	Periplocin and cardiac glycosides suppress the unfolded protein response
title_short	Periplocin and cardiac glycosides suppress the unfolded protein response
title_full	Periplocin and cardiac glycosides suppress the unfolded protein response
title_fullStr	Periplocin and cardiac glycosides suppress the unfolded protein response
title_full_unstemmed	Periplocin and cardiac glycosides suppress the unfolded protein response
title_sort	periplocin and cardiac glycosides suppress the unfolded protein response
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f4d5583a2ef44886af048e669358049f
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Periplocin and cardiac glycosides suppress the unfolded protein response

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