Tryptophanemia is controlled by a tryptophan-sensing mechanism ubiquitinating tryptophan 2,3-dioxygenase

Klaessens, Simon;Stroobant, Vincent;Hoffmann, Delia;Gyrd-Hansen, Mads;Van den Eynde, Benoit;et.al.
(2021) Proceedings of the National Academy of Sciences — Vol. 118, n° 23, p. e2022447118 (2021)

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Abstract
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 non-catalytic 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 4-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 non-metabolizable 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.
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Klaessens, S., Stroobant, V., Hoffmann, D., Gyrd-Hansen, M., Pilotte, L., Vigneron, N., De Plaen, E., & Van den Eynde, B. (2021). Tryptophanemia is controlled by a tryptophan-sensing mechanism ubiquitinating tryptophan 2,3-dioxygenase. Proceedings of the National Academy of Sciences, 118(23), e2022447118. https://doi.org/10.1073/pnas.2022447118 (Original work published 2021)