Ludwig Institute for Cancer Research, 1200 Brussels, Belgium.
de Duve Institute, Université catholique de Louvain, 1200 Brussels, Belgium.
Proc Natl Acad Sci U S A. 2021 Jun 8;118(23). doi: 10.1073/pnas.2022447118.
Maintaining stable tryptophan levels is required to control neuronal and immune activity. We report that tryptophan homeostasis is largely controlled by the stability of tryptophan 2,3-dioxygenase (TDO), the hepatic enzyme responsible for tryptophan catabolism. High tryptophan levels stabilize the active tetrameric conformation of TDO through binding noncatalytic exosites, resulting in rapid catabolism of tryptophan. In low tryptophan, the lack of tryptophan binding in the exosites destabilizes the tetramer into inactive monomers and dimers and unmasks a four-amino acid degron that triggers TDO polyubiquitination by SKP1-CUL1-F-box complexes, resulting in proteasome-mediated degradation of TDO and rapid interruption of tryptophan catabolism. The nonmetabolizable analog alpha-methyl-tryptophan stabilizes tetrameric TDO and thereby stably reduces tryptophanemia. Our results uncover a mechanism allowing a rapid adaptation of tryptophan catabolism to ensure quick degradation of excess tryptophan while preventing further catabolism below physiological levels. This ensures a tight control of tryptophanemia as required for both neurological and immune homeostasis.
维持色氨酸水平的稳定对于控制神经元和免疫活性是必需的。我们报告称，色氨酸稳态在很大程度上受色氨酸 2,3-双加氧酶（TDO）的稳定性控制，TDO 是负责色氨酸分解代谢的肝脏酶。高色氨酸水平通过结合非催化外位点稳定 TDO 的活性四聚体构象，导致色氨酸快速分解代谢。在低色氨酸中，外位点缺乏色氨酸结合会使四聚体解聚成非活性的单体和二聚体，并暴露出一个四氨基酸降解信号，该信号触发 SKP1-CUL1-F-box 复合物对 TDO 的多泛素化，导致 TDO 被蛋白酶体介导降解，并迅速中断色氨酸分解代谢。非代谢性类似物 alpha-甲基色氨酸稳定四聚体 TDO，从而稳定降低色氨酸血症。我们的结果揭示了一种机制，允许快速适应色氨酸分解代谢，以确保快速降解过量的色氨酸，同时防止在生理水平以下进一步分解代谢。这确保了色氨酸血症的严格控制，这是神经和免疫稳态所必需的。
