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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-83890-x |
| _version_ | 1818981941119025152 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T17:39:19Z |
| format | Article |
| id | doaj.art-244f0bfeceb04e76b0aedb99335c2c9a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-20T17:39:19Z |
| publishDate | 2021-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-244f0bfeceb04e76b0aedb99335c2c9a2022-12-21T19:31:08ZengNature PortfolioScientific Reports2045-23222021-02-0111111410.1038/s41598-021-83890-xThe ADP-binding kinase region of Ire1 directly contributes to its responsiveness to endoplasmic reticulum stressQuynh Giang Le0Yuki Ishiwata-Kimata1Thi Huong Phuong2Shigeto Fukunaka3Kenji Kohno4Yukio Kimata5Division of Bioscience, Graduate School of Science and Technology, Nara Institute of Science and TechnologyDivision of Bioscience, Graduate School of Science and Technology, Nara Institute of Science and TechnologyDivision of Bioscience, Graduate School of Science and Technology, Nara Institute of Science and TechnologyDivision of Bioscience, Graduate School of Science and Technology, Nara Institute of Science and TechnologyGraduate School of Life Science, University of HyogoDivision of Bioscience, Graduate School of Science and Technology, Nara Institute of Science and TechnologyAbstract 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.https://doi.org/10.1038/s41598-021-83890-x |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-021-83890-x |
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