| First Author | Lerner AG | Year | 2012 |
| Journal | Cell Metab | Volume | 16 |
| Issue | 2 | Pages | 250-64 |
| PubMed ID | 22883233 | Mgi Jnum | J:187377 |
| Mgi Id | MGI:5436336 | Doi | 10.1016/j.cmet.2012.07.007 |
| Citation | Lerner AG, et al. (2012) IRE1alpha Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress. Cell Metab 16(2):250-64 |
| abstractText | 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 IRE1alpha, an ER bifunctional kinase/endoribonuclease (RNase). Hyperactivated IRE1alpha 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 1beta (IL-1beta) secretion. Txnip gene deletion reduces pancreatic beta cell death during ER stress and suppresses diabetes caused by proinsulin misfolding in the Akita mouse. Finally, small molecule IRE1alpha RNase inhibitors suppress TXNIP production to block IL-1beta secretion. In summary, the IRE1alpha-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. |
