The ADP-binding kinase region of Ire1 directly contributes to its responsiveness to endoplasmic reticulum stress

Abstract Upon endoplasmic-reticulum (ER) stress, the ER-located transmembrane protein, Ire1, is autophosphorylated and acts as an endoribonuclease to trigger the unfolded protein response (UPR). Previous biochemical studies have shown that Ire1 exhibits strong endoribonuclease activity when its cyto...

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Autores principales:	Quynh Giang Le, Yuki Ishiwata-Kimata, Thi Huong Phuong, Shigeto Fukunaka, Kenji Kohno, Yukio Kimata
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/244f0bfeceb04e76b0aedb99335c2c9a
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spelling	oai:doaj.org-article:244f0bfeceb04e76b0aedb99335c2c9a2021-12-02T11:35:52ZThe ADP-binding kinase region of Ire1 directly contributes to its responsiveness to endoplasmic reticulum stress10.1038/s41598-021-83890-x2045-2322https://doaj.org/article/244f0bfeceb04e76b0aedb99335c2c9a2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83890-xhttps://doaj.org/toc/2045-2322Abstract Upon endoplasmic-reticulum (ER) stress, the ER-located transmembrane protein, Ire1, is autophosphorylated and acts as an endoribonuclease to trigger the unfolded protein response (UPR). Previous biochemical studies have shown that Ire1 exhibits strong endoribonuclease activity when its cytosolic kinase region captures ADP. Here, we asked how this event contributes to the regulation of Ire1 activity. At the beginning of this study, we obtained a luminal-domain mutant of Saccharomyces cerevisiae Ire1, deltaIdeltaIIIdeltaV/Y225H Ire1, which is deduced to be controlled by none of the luminal-side regulatory events. ER-stress responsiveness of deltaIdeltaIIIdeltaV/Y225H Ire1 was largely compromised by a further mutation on the kinase region, D797N/K799N, which allows Ire1 to be activated without capturing ADP. Therefore, in addition to the ER-luminal domain of Ire1, which monitors ER conditions, the kinase region is directly involved in the ER-stress responsiveness of Ire1. We propose that potent ER stress harms cells’ “vividness”, increasing the cytosolic ADP/ATP ratio, and eventually strongly activates Ire1. This mechanism seems to contribute to the suppression of inappropriately potent UPR under weak ER-stress conditions.Quynh Giang LeYuki Ishiwata-KimataThi Huong PhuongShigeto FukunakaKenji KohnoYukio KimataNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Quynh Giang Le Yuki Ishiwata-Kimata Thi Huong Phuong Shigeto Fukunaka Kenji Kohno Yukio Kimata The ADP-binding kinase region of Ire1 directly contributes to its responsiveness to endoplasmic reticulum stress
description	Abstract Upon endoplasmic-reticulum (ER) stress, the ER-located transmembrane protein, Ire1, is autophosphorylated and acts as an endoribonuclease to trigger the unfolded protein response (UPR). Previous biochemical studies have shown that Ire1 exhibits strong endoribonuclease activity when its cytosolic kinase region captures ADP. Here, we asked how this event contributes to the regulation of Ire1 activity. At the beginning of this study, we obtained a luminal-domain mutant of Saccharomyces cerevisiae Ire1, deltaIdeltaIIIdeltaV/Y225H Ire1, which is deduced to be controlled by none of the luminal-side regulatory events. ER-stress responsiveness of deltaIdeltaIIIdeltaV/Y225H Ire1 was largely compromised by a further mutation on the kinase region, D797N/K799N, which allows Ire1 to be activated without capturing ADP. Therefore, in addition to the ER-luminal domain of Ire1, which monitors ER conditions, the kinase region is directly involved in the ER-stress responsiveness of Ire1. We propose that potent ER stress harms cells’ “vividness”, increasing the cytosolic ADP/ATP ratio, and eventually strongly activates Ire1. This mechanism seems to contribute to the suppression of inappropriately potent UPR under weak ER-stress conditions.
format	article
author	Quynh Giang Le Yuki Ishiwata-Kimata Thi Huong Phuong Shigeto Fukunaka Kenji Kohno Yukio Kimata
author_facet	Quynh Giang Le Yuki Ishiwata-Kimata Thi Huong Phuong Shigeto Fukunaka Kenji Kohno Yukio Kimata
author_sort	Quynh Giang Le
title	The ADP-binding kinase region of Ire1 directly contributes to its responsiveness to endoplasmic reticulum stress
title_short	The ADP-binding kinase region of Ire1 directly contributes to its responsiveness to endoplasmic reticulum stress
title_full	The ADP-binding kinase region of Ire1 directly contributes to its responsiveness to endoplasmic reticulum stress
title_fullStr	The ADP-binding kinase region of Ire1 directly contributes to its responsiveness to endoplasmic reticulum stress
title_full_unstemmed	The ADP-binding kinase region of Ire1 directly contributes to its responsiveness to endoplasmic reticulum stress
title_sort	adp-binding kinase region of ire1 directly contributes to its responsiveness to endoplasmic reticulum stress
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/244f0bfeceb04e76b0aedb99335c2c9a
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The ADP-binding kinase region of Ire1 directly contributes to its responsiveness to endoplasmic reticulum stress

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