IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress
When unfolded proteins accumulate to irremediably high levels within the endoplasmic reticulum (ER), intracellular signaling pathways called the unfolded protein response (UPR) become hyperactivated to cause programmed cell death. We discovered that thioredoxin-interacting protein (TXNIP) is a criti...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Elsevier
2017
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| Online Access: | http://hdl.handle.net/1721.1/112193 https://orcid.org/0000-0002-6365-8673 |
| _version_ | 1826199790527971328 |
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| author | Lerner, Alana G. Upton, John-Paul Praveen, P.V.K. Ghosh, Rajarshi Nakagawa, Yoshimi Igbaria, Aeid Shen, Sarah Nguyen, Vinh Backes, Bradley J. Heintz, Nathaniel Greengard, Paul Hui, Simon Tang, Qizhi Trusina, Ala Oakes, Scott A. Papa, Feroz R. Heiman, Myriam |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Lerner, Alana G. Upton, John-Paul Praveen, P.V.K. Ghosh, Rajarshi Nakagawa, Yoshimi Igbaria, Aeid Shen, Sarah Nguyen, Vinh Backes, Bradley J. Heintz, Nathaniel Greengard, Paul Hui, Simon Tang, Qizhi Trusina, Ala Oakes, Scott A. Papa, Feroz R. Heiman, Myriam |
| author_sort | Lerner, Alana G. |
| collection | MIT |
| description | When unfolded proteins accumulate to irremediably high levels within the endoplasmic reticulum (ER), intracellular signaling pathways called the unfolded protein response (UPR) become hyperactivated to cause programmed cell death. We discovered that thioredoxin-interacting protein (TXNIP) is a critical node in this "terminal UPR." TXNIP becomes rapidly induced by IRE1α, an ER bifunctional kinase/endoribonuclease (RNase). Hyperactivated IRE1α increases TXNIP mRNA stability by reducing levels of a TXNIP destabilizing microRNA, miR-17. In turn, elevated TXNIP protein activates the NLRP3 inflammasome, causing procaspase-1 cleavage and interleukin 1β (IL-1β) secretion. Txnip gene deletion reduces pancreatic β cell death during ER stress and suppresses diabetes caused by proinsulin misfolding in the Akita mouse. Finally, small molecule IRE1α RNase inhibitors suppress TXNIP production to block IL-1β secretion. In summary, the IRE1α-TXNIP pathway is used in the terminal UPR to promote sterile inflammation and programmed cell death and may be targeted to develop effective treatm ents for cell degenerative diseases. |
| first_indexed | 2024-09-23T11:25:49Z |
| format | Article |
| id | mit-1721.1/112193 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T11:25:49Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1121932022-09-27T19:29:11Z IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress Lerner, Alana G. Upton, John-Paul Praveen, P.V.K. Ghosh, Rajarshi Nakagawa, Yoshimi Igbaria, Aeid Shen, Sarah Nguyen, Vinh Backes, Bradley J. Heintz, Nathaniel Greengard, Paul Hui, Simon Tang, Qizhi Trusina, Ala Oakes, Scott A. Papa, Feroz R. Heiman, Myriam Broad Institute of MIT and Harvard Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Heiman, Myriam When unfolded proteins accumulate to irremediably high levels within the endoplasmic reticulum (ER), intracellular signaling pathways called the unfolded protein response (UPR) become hyperactivated to cause programmed cell death. We discovered that thioredoxin-interacting protein (TXNIP) is a critical node in this "terminal UPR." TXNIP becomes rapidly induced by IRE1α, an ER bifunctional kinase/endoribonuclease (RNase). Hyperactivated IRE1α increases TXNIP mRNA stability by reducing levels of a TXNIP destabilizing microRNA, miR-17. In turn, elevated TXNIP protein activates the NLRP3 inflammasome, causing procaspase-1 cleavage and interleukin 1β (IL-1β) secretion. Txnip gene deletion reduces pancreatic β cell death during ER stress and suppresses diabetes caused by proinsulin misfolding in the Akita mouse. Finally, small molecule IRE1α RNase inhibitors suppress TXNIP production to block IL-1β secretion. In summary, the IRE1α-TXNIP pathway is used in the terminal UPR to promote sterile inflammation and programmed cell death and may be targeted to develop effective treatm ents for cell degenerative diseases. 2017-11-15T16:47:44Z 2017-11-15T16:47:44Z 2012-08 2012-06 2017-11-13T17:57:17Z Article http://purl.org/eprint/type/JournalArticle 1550-4131 1932-7420 http://hdl.handle.net/1721.1/112193 Lerner, Alana G. et al. “IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death Under Irremediable ER Stress.” Cell Metabolism 16, 2 (August 2012): 250–264 © 2012 Elsevier Inc https://orcid.org/0000-0002-6365-8673 http://dx.doi.org/10.1016/j.cmet.2012.07.007 Cell Metabolism Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Lerner, Alana G. Upton, John-Paul Praveen, P.V.K. Ghosh, Rajarshi Nakagawa, Yoshimi Igbaria, Aeid Shen, Sarah Nguyen, Vinh Backes, Bradley J. Heintz, Nathaniel Greengard, Paul Hui, Simon Tang, Qizhi Trusina, Ala Oakes, Scott A. Papa, Feroz R. Heiman, Myriam IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress |
| title | IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress |
| title_full | IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress |
| title_fullStr | IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress |
| title_full_unstemmed | IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress |
| title_short | IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress |
| title_sort | ire1α induces thioredoxin interacting protein to activate the nlrp3 inflammasome and promote programmed cell death under irremediable er stress |
| url | http://hdl.handle.net/1721.1/112193 https://orcid.org/0000-0002-6365-8673 |
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