Cytosolic thioredoxin 1 (Trx1, TXN, TRX) is a central player in redox control. Thioredoxin interacting protein (TXNIP), an α-arrestin regulating glucose metabolism and inflammation, is widely regarded to inhibit TRX activity. However, the interactions between the two proteins across various cellular contexts remain poorly understood; in addition, only a limited number of studies have yet been conducted in human primary cells. We thus aimed here to investigate the functional relationship between TRX and TXNIP in human primary cells. We studied whether TXNIP inhibits TRX cellular activity in these primary cells and how this interaction influences cellular redox biology or glucose metabolism.
Results:
In primary cells, TXNIP deficiency did not increase cellular TRX activity. Instead, TXNIP deficiency elevated PGC-1α and PDK4 transcripts, increased PDHA1 Ser293 phosphorylation, and raised basal GLUT4, consistent with enhanced glucose uptake and restrained flux through the pyruvate dehydrogenase complex. Conversely, lowering TRX expression levels triggered higher TXNIP levels. This in turn correlated with suppressed transcripts for PGC-1α and PDK4, a lower extent of PDHA1 phosphorylation at Ser293, and decreased glucose uptake.
Innovation:
Our findings suggest that TXNIP, against common belief, may not necessarily be an endogenous inhibitor of TRX but, rather, that TRX can be an inhibitor of TXNIP.
Conclusion:
This study reveals that the key intracellular redox protein TRX inversely regulates TXNIP, suggesting that modulation of the TRX system may provide a previously unrecognized therapeutic avenue for modulation of glucose metabolism. Antioxid. Redox Signal. 44, 643–660.
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