ERK-dependent proteasome degradation of Txnip regulates thioredoxin oxidoreductase activity

• Published in: The Journal of biological chemistry Vol. 294; no. 36; pp. 13336 - 13343
• Main Authors: Kelleher, Zachary T., Wang, Chunbo, Forrester, Michael T., Foster, Matthew W., Marshall, Harvey E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.09.2019; American Society for Biochemistry and Molecular Biology
• Subjects: A549 Cells; Carrier Proteins - metabolism; Cell Biology; epithelial cell; Extracellular Signal-Regulated MAP Kinases - metabolism; extracellular-signal-regulated kinase (ERK); Humans; Mass Spectrometry; nitrosative stress; oxidative stress; proteasome; Proteasome Endopeptidase Complex - metabolism; thioredoxin; Thioredoxin-Disulfide Reductase - metabolism; Tumor Cells, Cultured; ubiquitylation (ubiquitination); extracellular-signal-regulated kinase (ERK); proteasome; ubiquitylation (ubiquitination); nitrosative stress; thioredoxin; epithelial cell; oxidative stress
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.007733

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.