title: IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress.
abstract: 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 treatments for cell degenerative diseases.
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Alana G
authors.initials: AG
authors.lastname: Lerner
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Upton
authors.forename: P V K
authors.initials: PV
authors.lastname: Praveen
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Ghosh
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Aeid
authors.initials: A
authors.lastname: Igbaria
authors.forename: Sarah
authors.initials: S
authors.lastname: Shen
authors.forename: Vinh
authors.initials: V
authors.lastname: Nguyen
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Backes
authors.forename: Myriam
authors.initials: M
authors.lastname: Heiman
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Heintz
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Simon
authors.initials: S
authors.lastname: Hui
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Tang
authors.forename: Ala
authors.initials: A
authors.lastname: Trusina
authors.forename: Scott A
authors.initials: SA
authors.lastname: Oakes
authors.forename: Feroz R
authors.initials: FR
authors.lastname: Papa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013879:Thioredoxins / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C445672:Txnip protein, mouse; D013879:Thioredoxins; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases