Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome

By C. M. Oslowski, T. Hara, B. O'Sullivan-Murphy, Kohsuke Kanekura, Simin Lu, M. Hara, S. Ishigaki, Lihua Julie Zhu, Emiko Hayashi, S. Hui and 4 more. Cell Metabolism, 2012

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SUMMARY 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.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/09f5277681dda5b7a8173218638776a5bf8d7916

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Citations in the corpus

Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease (2015, positive): “It is also possible that the increased sensitivity of Nrf2−/− mice to proinflammatory stimuli is a consequence of an increased susceptibility to ER stress and may occur via induction of TXN-interacting protein, downstream of the PERK and IRE1 pathways, to cause increased production of interleukin-1β”
ER stress-induced cell death mechanisms. (2013, background): “In turn, TXNIP promoted IL-1β production by the NLRP3 inflammasome and in pancreatic β-cells [107].”
AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1 (2013, background): “Given that the initial identification of TXNIP as a vitamin D3 upregulated protein (VDUP1) in HL-60 cells (Chen and DeLuca, 1994), many factors were found to regulate TXNIP messenger RNA (mRNA) levels (Baker et al., 2008; Billiet et al., 2008; Kim et al., 2004; Lerner et al., 2012; Oslowski et al., ”
Redox Regulation of NLRP3 Inflammasomes: ROS as Trigger or Effector? (2015, background): “Contradictorily, the UPR and the IRE1α and PERK pathways are necessary for IL-1β secretion in pancreatic β cells, where thioredoxin-interacting protein (TXNIP) acts as the link between ER stress, NLRP3 inflammasome activation, and inflammation related to diabetes (66,101).”