Title: TXNIP Switches Tracks toward a Terminal UPR
Abstract: During the progression of diabetes, crosstalk between ER stress and inflammation controls islet cell fate. In this issue, Lerner et al., 2012Lerner A.G. Upton J.-P. Praveen P.V.K. Ghosh R. Nakagawa Y. Shen S. Nguyen V. Backes B.J. Heiman M. Heintz N. et al.Cell Metab. 2012; 18 (this issue): 250-264Abstract Full Text Full Text PDF Scopus (595) Google Scholar and Oslowski et al., 2012Oslowski C.M. Hara T. O'Sullivan-Murphy B. Kanekura K. Lu S. Hara M. Ishigaki S. Zhu L.J. Hayashi E. Hui S.T. et al.Cell Metab. 2012; 18 (this issue): 265-273Abstract Full Text Full Text PDF Scopus (482) Google Scholar discover that thioredoxin-interacting protein (TXNIP) is a regulatory switch connecting the terminal unfolded protein response (UPR) and NLRP3 inflammasome to mediate β cell death. During the progression of diabetes, crosstalk between ER stress and inflammation controls islet cell fate. In this issue, Lerner et al., 2012Lerner A.G. Upton J.-P. Praveen P.V.K. Ghosh R. Nakagawa Y. Shen S. Nguyen V. Backes B.J. Heiman M. Heintz N. et al.Cell Metab. 2012; 18 (this issue): 250-264Abstract Full Text Full Text PDF Scopus (595) Google Scholar and Oslowski et al., 2012Oslowski C.M. Hara T. O'Sullivan-Murphy B. Kanekura K. Lu S. Hara M. Ishigaki S. Zhu L.J. Hayashi E. Hui S.T. et al.Cell Metab. 2012; 18 (this issue): 265-273Abstract Full Text Full Text PDF Scopus (482) Google Scholar discover that thioredoxin-interacting protein (TXNIP) is a regulatory switch connecting the terminal unfolded protein response (UPR) and NLRP3 inflammasome to mediate β cell death. Excessive or protracted inflammation triggered by a chronic accumulation of metabolic factors is a hallmark of many degenerative diseases, including both type 1 and type 2 diabetes. Inflammation is the first means by which the immune system limits cell injury and damage in response to environmental irritants, pathogens, and infectious agents. Yet left unchecked, the inflammatory process turns toward cellular destruction and pyroptosis, a form of programmed cell death dependent on caspase-1 activation and proinflammatory cytokines. How the inflammatory process switches from stress remediation toward death pathways is a mystery. Recently, efforts directed at mechanisms linking metabolic overload with self-destruction and diabetes progression have discovered that uncontrolled endoplasmic reticulum (ER) stress is associated with a sterile but lethal inflammatory response (Hummasti and Hotamisligil, 2010Hummasti S. Hotamisligil G.S. Circ. Res. 2010; 107: 579-591Crossref PubMed Scopus (328) Google Scholar). The molecular connection between these two biological responses, now identified in this issue, is thioredoxin-interacting protein (TXNIP) (Lerner et al., 2012Lerner A.G. Upton J.-P. Praveen P.V.K. Ghosh R. Nakagawa Y. Shen S. Nguyen V. Backes B.J. Heiman M. Heintz N. et al.Cell Metab. 2012; 18 (this issue): 250-264Abstract Full Text Full Text PDF Scopus (595) Google Scholar; Oslowski et al., 2012Oslowski C.M. Hara T. O'Sullivan-Murphy B. Kanekura K. Lu S. Hara M. Ishigaki S. Zhu L.J. Hayashi E. Hui S.T. et al.Cell Metab. 2012; 18 (this issue): 265-273Abstract Full Text Full Text PDF Scopus (482) Google Scholar). Oxidative stress disrupts ER homeostasis, activating a multifaceted signaling program called the unfolded protein response (UPR). Three transmembrane sensors, namely inositol-requiring enzyme 1 (IRE1), PKR-like ER-resident kinase (PERK), and activating transcription factor 6 (ATF6) together elicit a program of gene expression designed to alleviate a buildup of misfolded proteins and regain ER homeostasis. Hyperactivation of the UPR to irremediable ER stress leads to inflammation and cell death, and in the case of the β cell, culminates in diabetes. In the current articles (Lerner et al., 2012Lerner A.G. Upton J.-P. Praveen P.V.K. Ghosh R. Nakagawa Y. Shen S. Nguyen V. Backes B.J. Heiman M. Heintz N. et al.Cell Metab. 2012; 18 (this issue): 250-264Abstract Full Text Full Text PDF Scopus (595) Google Scholar; Oslowski et al., 2012Oslowski C.M. Hara T. O'Sullivan-Murphy B. Kanekura K. Lu S. Hara M. Ishigaki S. Zhu L.J. Hayashi E. Hui S.T. et al.Cell Metab. 2012; 18 (this issue): 265-273Abstract Full Text Full Text PDF Scopus (482) Google Scholar), two of the three UPR sensors, namely IRE1α and PERK, play critical roles in regulating the expression of TXNIP. Treatment with pharmacologic agents that cause ER stress increased TXNIP mRNA levels in wild-type and ATF6−/− mouse embryonic fibroblasts but not in cells deficient for IRE1α or PERK (Lerner et al., 2012Lerner A.G. Upton J.-P. Praveen P.V.K. Ghosh R. Nakagawa Y. Shen S. Nguyen V. Backes B.J. Heiman M. Heintz N. et al.Cell Metab. 2012; 18 (this issue): 250-264Abstract Full Text Full Text PDF Scopus (595) Google Scholar; Oslowski et al., 2012Oslowski C.M. Hara T. O'Sullivan-Murphy B. Kanekura K. Lu S. Hara M. Ishigaki S. Zhu L.J. Hayashi E. Hui S.T. et al.Cell Metab. 2012; 18 (this issue): 265-273Abstract Full Text Full Text PDF Scopus (482) Google Scholar). Similarly, siRNA-mediated knockdown of IRE1α or PERK, but not ATF6, in insulinoma cells precluded TXNIP mRNA expression following ER stress (Oslowski et al., 2012Oslowski C.M. Hara T. O'Sullivan-Murphy B. Kanekura K. Lu S. Hara M. Ishigaki S. Zhu L.J. Hayashi E. Hui S.T. et al.Cell Metab. 2012; 18 (this issue): 265-273Abstract Full Text Full Text PDF Scopus (482) Google Scholar). The lack of ATF6 involvement in regulating TXNIP expression emphasizes that the relationship between ER stress and inflammation occurs independent of the tripartite UPR. These findings are significant in that each sensor can have distinct functions implementing the UPR, with IRE1α and PERK each participating in cell destruction during unabated stress. Urano and colleagues (Oslowski et al., 2012Oslowski C.M. Hara T. O'Sullivan-Murphy B. Kanekura K. Lu S. Hara M. Ishigaki S. Zhu L.J. Hayashi E. Hui S.T. et al.Cell Metab. 2012; 18 (this issue): 265-273Abstract Full Text Full Text PDF Scopus (482) Google Scholar) then went further to identify the PERK-regulated transcription factors controlling TXNIP expression. During ER stress, PERK phosphorylates eukaryotic initiation factor 2 (eIF2), reducing global translation. This action lowers the influx of proteins into the ER and directs energy toward preferentially translating select mRNAs, such as ATF4, which promotes the expression of genes controlling redox status plus facilitates induction of the other arms of the UPR (Teske et al., 2011Teske B.F. Wek S.A. Bunpo P. Cundiff J.K. McClintick J.N. Anthony T.G. Wek R.C. Mol. Biol. Cell. 2011; 22: 4390-4405Crossref PubMed Scopus (252) Google Scholar). However, following a screen of transcription factors regulated by PERK, it was concluded that ATF4 was not a significant regulator of TXNIP synthesis. Rather, a related transcription factor called ATF5, also subject to translational control by eIF2 phosphorylation, was shown via chromatin immunoprecipitation analysis to bind the TNXIP promoter during ER stress. These data demonstrate that the PERK arm of the UPR functions primarily to increase TXNIP transcription during ER stress. The contribution of IRE1α in the regulation of TXNIP expression depends on its dual functions as both a protein kinase and an endoribonuclease. Upon remediable ER stress, IRE1α kinase domain is autophosphorylated, restricting its carboxy-terminal ribonuclease activity toward the mRNA encoding XBP-1 (X-box-binding protein 1). This splicing event produces a potent transcription factor that is important for triggering adaptive functions such as ER-to-Golgi protein transport, protein folding, and ER-associated degradation (ERAD) of misfolded proteins. Under conditions of irremediable ER stress, IRE1α ribonuclease activity becomes less discriminate (Han et al., 2009Han D. Lerner A.G. Vande Walle L. Upton J.P. Xu W. Hagen A. Backes B.J. Oakes S.A. Papa F.R. Cell. 2009; 138: 562-575Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar), and as described in this issue (Lerner et al., 2012Lerner A.G. Upton J.-P. Praveen P.V.K. Ghosh R. Nakagawa Y. Shen S. Nguyen V. Backes B.J. Heiman M. Heintz N. et al.Cell Metab. 2012; 18 (this issue): 250-264Abstract Full Text Full Text PDF Scopus (595) Google Scholar), triggers decay of mi-R17, a regulator of TXNIP mRNA stability. Under normal conditions, TXNIP mRNA half-life is short, but during ER stress it becomes stabilized. Increased mRNA stability alone can lead to elevated mRNA expression, but when combined with PERK-mediated increase in transcription, a steeper induction results (Figure 1). This finding extends previous work by this group and others (Han et al., 2009Han D. Lerner A.G. Vande Walle L. Upton J.P. Xu W. Hagen A. Backes B.J. Oakes S.A. Papa F.R. Cell. 2009; 138: 562-575Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar; Hollien et al., 2009Hollien J. Lin J.H. Li H. Stevens N. Walter P. Weissman J.S. J. Cell Biol. 2009; 186: 323-331Crossref PubMed Scopus (698) Google Scholar) by showing how IRE1α-dependent decay of mi-R17 tailors the transcriptome to ER stress. To validate these concepts in vivo, islets from the "Akita" mouse (Ins2WT/C96Y), a model of diabetes caused by proinsulin misfolding, demonstrated reduced mi-R17 and elevated TXNIP mRNA. Furthermore, pancreatic islets from TXNIP−/− mice showed reduced cell death in response to ER stress agents and genetic deletion of TXNIP in Akita mice protected them from hyperglycemia (Lerner et al., 2012Lerner A.G. Upton J.-P. Praveen P.V.K. Ghosh R. Nakagawa Y. Shen S. Nguyen V. Backes B.J. Heiman M. Heintz N. et al.Cell Metab. 2012; 18 (this issue): 250-264Abstract Full Text Full Text PDF Scopus (595) Google Scholar). This study reveals that regulated mRNA stability of TXNIP contributes importantly to cell fate decisions during ER stress. Chronic excess of metabolic factors (e.g., glucose, lipids) promotes formation of large, multiprotein complexes called inflammasomes. NOD-like receptor (NLR) proteins are key components of inflammasomes, facilitating caspase-1 maturation and secretion of cytokines in response to cellular danger (Schroder et al., 2010Schroder K. Zhou R. Tschopp J. Science. 2010; 327: 296-300Crossref PubMed Scopus (847) Google Scholar; Vandanmagsar et al., 2011Vandanmagsar B. Youm Y.H. Ravussin A. Galgani J.E. Stadler K. Mynatt R.L. Ravussin E. Stephens J.M. Dixit V.D. Nat. Med. 2011; 17: 179-188Crossref PubMed Scopus (1792) Google Scholar). The NLRP3 inflammasome in particular functions as a sensor of metabolic stress activated by high glucose and reactive oxygen species (ROS) (Zhou et al., 2010Zhou R. Tardivel A. Thorens B. Choi I. Tschopp J. Nat. Immunol. 2010; 11: 136-140Crossref PubMed Scopus (1854) Google Scholar). Thanks to the current studies (Lerner et al., 2012Lerner A.G. Upton J.-P. Praveen P.V.K. Ghosh R. Nakagawa Y. Shen S. Nguyen V. Backes B.J. Heiman M. Heintz N. et al.Cell Metab. 2012; 18 (this issue): 250-264Abstract Full Text Full Text PDF Scopus (595) Google Scholar; Oslowski et al., 2012Oslowski C.M. Hara T. O'Sullivan-Murphy B. Kanekura K. Lu S. Hara M. Ishigaki S. Zhu L.J. Hayashi E. Hui S.T. et al.Cell Metab. 2012; 18 (this issue): 265-273Abstract Full Text Full Text PDF Scopus (482) Google Scholar), the relationship between ER stress and the inflammasome is now clarified. With increased levels of TXNIP, the antioxidant function of thioredoxins are dampened, further increasing ROS, and binding of TXNIP to NLRP3 is promoted, activating caspase-1 cleavage, interleukin (IL)-1β secretion and pyroptosis. In support of this, inducing TXNIP expression increased caspase-3 cleavage and cell death in insulinoma cells, and pretreating human primary islets with IL-1 receptor antagonist reduced IL-1β and IL-6 expression and caspase-3/-7 activity to ER stress agents (Oslowski et al., 2012Oslowski C.M. Hara T. O'Sullivan-Murphy B. Kanekura K. Lu S. Hara M. Ishigaki S. Zhu L.J. Hayashi E. Hui S.T. et al.Cell Metab. 2012; 18 (this issue): 265-273Abstract Full Text Full Text PDF Scopus (482) Google Scholar). TXNIP is therefore suggested to serve as a wye switch that can redirect the cell-fate railway track from an adaptive outcome to a terminal UPR (Figure 1). Human conditions such as Wolfram syndrome type 1 ascribe loss of β cells to unmitigated ER stress and activation of the UPR. Significant levels of ER stress in β cells can also be the consequence of continued exposure to free fatty acids and cytokines (Hummasti and Hotamisligil, 2010Hummasti S. Hotamisligil G.S. Circ. Res. 2010; 107: 579-591Crossref PubMed Scopus (328) Google Scholar). By identifying a novel path in the pathogenesis of diabetes, the current studies are foundational to the development of new treatment approaches. Importantly, Lerner et al., 2012Lerner A.G. Upton J.-P. Praveen P.V.K. Ghosh R. Nakagawa Y. Shen S. Nguyen V. Backes B.J. Heiman M. Heintz N. et al.Cell Metab. 2012; 18 (this issue): 250-264Abstract Full Text Full Text PDF Scopus (595) Google Scholar show that a drug that inhibits IRE1α endoribonuclease activity without affecting its kinase activity (STF-083010) reduces TXNIP expression and inflammasome activation in β cells. It is hopeful that this or other novel small-molecule inhibitors of this pathway can be tailored toward the treatment of diabetes and/or other degenerative diseases. Thioredoxin-Interacting Protein Mediates ER Stress-Induced β Cell Death through Initiation of the InflammasomeOslowski et al.Cell MetabolismAugust 08, 2012In BriefRecent 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. Full-Text PDF Open ArchiveIRE1α Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER StressLerner et al.Cell MetabolismAugust 08, 2012In BriefWhen 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. Full-Text PDF Open Archive