Journal of Biological Chemistry
Volume 294, Issue 36, 6 September 2019, Pages 13336-13343
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Cell Biology
ERK-dependent proteasome degradation of Txnip regulates thioredoxin oxidoreductase activityERK regulation of Txnip proteasome degradation

https://doi.org/10.1074/jbc.RA119.007733Get rights and content
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Dynamic control of thioredoxin (Trx) oxidoreductase activity is essential for balancing the need of cells to rapidly respond to oxidative/nitrosative stress and to temporally regulate thiol-based redox signaling. We have previously shown that cytokine stimulation of the respiratory epithelium induces a precipitous decline in cell S-nitrosothiol, which depends upon enhanced Trx activity and proteasome-mediated degradation of Txnip (thioredoxin-interacting protein). We now show that tumor necrosis factor-α–induced Txnip degradation in A549 respiratory epithelial cells is regulated by the extracellular signal-regulated protein kinase (ERK) mitogen-activated protein kinase pathway and that ERK inhibition augments both intracellular reactive oxygen species and S-nitrosothiol. ERK-dependent Txnip ubiquitination and proteasome degradation depended upon phosphorylation of a PXTP motif threonine (Thr349) located within the C-terminal α-arrestin domain and proximal to a previously characterized E3 ubiquitin ligase–binding site. Collectively, these findings demonstrate the ERK mitogen-activated protein kinase pathway to be integrally involved in regulating Trx oxidoreductase activity and that the regulation of Txnip lifetime via ERK-dependent phosphorylation is an important mediator of this effect.

thioredoxin
extracellular-signal-regulated kinase (ERK)
proteasome
ubiquitylation (ubiquitination)
nitrosative stress
oxidative stress
epithelial cell

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This work was supported by National Institutes of Health Grant HL092994 (to H. E. M.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This article contains Figs. S1–S4.