Post-translational regulation of IDO-1 by uremic toxins
Embargo Date
2028-03-31
OA Version
Citation
Abstract
Indolamine, 2, 3 dioxygenase (IDO-1) is a key rate limiting enzyme in the synthesis of kynurenine from tryptophan. IDO-1 is expressed mostly in endothelium, vascular smooth muscle cells and other organ systems. Previous work has shown IDO-1 is an important regulator of thrombosis in chronic kidney disease. Indoxyl sulfate, a uremic solute retained in patients of CKD, upregulates IDO-1 expression. We hypothesized that indoxyl sulfate (IS) suppresses IDO-1 ubiquitination and degradation. Here we show that IS, at the levels found in CKD patients, upregulates IDO-1. IS increases the half-life of IDO-1, suggesting an increase in stability. Screening of putative E3 ligases showed that F-box/WD Repeat-Containing Protein 4 (FBXW4), a Skp, Cullen, F-box containing complex (SCF) E3 ligase, interacts with IDO-1, downregulates IDO-1 protein expression, and shortens the half-life of IDO-1. This effect is mitigated in the presence of IS. This data suggests that FBXW4 is a candidate E3 ligase for IDO-1 and that IS may mediate its regulation on IDO-1 through FBXW4. This body of work for the first time shows a novel E3 ligase for IDO-1, especially in the context of the uremic milieu.