The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress
Open accessAbstract
SUMMARY 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 micro-RNA, miR-17. In turn, elevated TXNIP protein activates the NLRP3 inflammasome, causing Caspase-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 treatments for cell degenerative diseases.
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Cites
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Inflammasomes in health and disease
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Self-citationTargeted disruption of the chop gene delays endoplasmic reticulum stress-mediated diabetes
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TXNIP regulates peripheral glucose metabolism in humans
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Cited by
Mechanisms, regulation and functions of the unfolded protein response
Hetz, C., Zhang, K., & Kaufman, R. J. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0250-z · Cited by 2,666
Reactive Oxygen Species in Metabolic and Inflammatory Signaling
Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q., & Griendling, K. K. (2018) · Circulation Research · doi:10.1161/circresaha.117.311401 · Cited by 2,081
ER stress-induced cell death mechanisms
Sano, R., & Reed, J. C. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.06.028 · Cited by 1,988
Protein misfolding in the endoplasmic reticulum as a conduit to human disease
Wang, M., & Kaufman, R. J. (2016) · Nature · doi:10.1038/nature17041 · Cited by 1,630
The Unfolded Protein Response and Cell Fate Control
Hetz, C., & Papa, F. R. (2018) · Molecular Cell · doi:10.1016/j.molcel.2017.06.017 · Cited by 1,544
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Metadata
- Authors
- Lerner, A. G., Upton, J.-P., Praveen, P. V. K., Ghosh, R., Nakagawa, Y., Igbaria, A., Shen, S., Nguyen, V., Backes, B. J., Heiman, M., Heintz, N., Greengard, P., Hui, S., Tang, Q., Trusina, A., Oakes, S. A., & Papa, F. R.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 16
- Issue
- 2
- Pages
- 250-264
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2147810846
- Cited by
- 846
- References
- 8
- FWCI
- 23.10
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Lerner, A. G., Upton, J.-P., Praveen, P. V. K., Ghosh, R., Nakagawa, Y., Igbaria, A., Shen, S., Nguyen, V., Backes, B. J., Heiman, M., Heintz, N., Greengard, P., Hui, S., Tang, Q., Trusina, A., Oakes, S. A., & Papa, F. R. (2012). IRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress. Cell Metabolism. https://doi.org/10.1016/j.cmet.2012.07.007
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