title: Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome.
abstract: Recent clinical and experimental evidence suggests that endoplasmic reticulum (ER) stress contributes to the life-and-death decisions of β cells during the progression of type 1 and type 2 diabetes. Although crosstalk between inflammation and ER stress has been suggested to play a significant role in β cell dysfunction and death, a key molecule connecting ER stress to inflammation has not been identified. Here we report that thioredoxin-interacting protein (TXNIP) is a critical signaling node that links ER stress and inflammation. TXNIP is induced by ER stress through the PERK and IRE1 pathways, induces IL-1β mRNA transcription, activates IL-1β production by the NLRP3 inflammasome, and mediates ER stress-mediated β cell death. Collectively, our results suggest that TXNIP is a potential therapeutic target for diabetes and ER stress-related human diseases such as Wolfram syndrome.
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Oslowski
authors.forename: Takashi
authors.initials: T
authors.lastname: Hara
authors.forename: Bryan
authors.initials: B
authors.lastname: O'Sullivan-Murphy
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kanekura
authors.forename: Simin
authors.initials: S
authors.lastname: Lu
authors.forename: Mariko
authors.initials: M
authors.lastname: Hara
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.forename: Lihua J
authors.initials: LJ
authors.lastname: Zhu
authors.forename: Emiko
authors.initials: E
authors.lastname: Hayashi
authors.forename: Simon T
authors.initials: ST
authors.lastname: Hui
authors.forename: Dale
authors.initials: D
authors.lastname: Greiner
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Rita
authors.initials: R
authors.lastname: Bortell
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D003920:Diabetes Mellitus / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D058847:Inflammasomes / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D053583:Interleukin-1beta / Q000378:metabolism; D008156:Luciferases; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008156:Luciferases; D008565:Membrane Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017346:Protein Serine-Threonine Kinases; D013879:Thioredoxins; D019892:eIF-2 Kinase; C492716:Nlrp3 protein, mouse; C445672:Txnip protein, mouse; C486556:Ern2 protein, mouse