title: Autophagy induction by tetrahydrobiopterin deficiency.
abstract: Tetrahydrobiopterin (BH₄) deficiency is a genetic disorder associated with a variety of metabolic syndromes such as phenylketonuria (PKU). In this article, the signaling pathway by which BH₄ deficiency inactivates mTORC1 leading to the activation of the autophagic pathway was studied utilizing BH₄-deficient Spr(-/-) mice generated by the knockout of the gene encoding sepiapterin reductase (SR) catalyzing BH₄ synthesis. We found that mTORC1 signaling was inactivated and autophagic pathway was activated in tissues from Spr(-/-) mice. This study demonstrates that tyrosine deficiency causes mTORC1 inactivation and subsequent activation of autophagic pathway in Spr(-/-) mice. Therapeutic tyrosine diet completely rescued dwarfism and mTORC1 inhibition but inactivated autophagic pathway in Spr(-/-) mice. Tyrosine-dependent inactivation of mTORC1 was further supported by mTORC1 inactivation in Pah(enu2) mouse model lacking phenylalanine hydroxylase (Pah). NIH3T3 cells grown under the condition of tyrosine restriction exhibited autophagy induction. However, mTORC1 activation by RhebQ64L, a positive regulator of mTORC1, inactivated autophagic pathway in NIH3T3 cells under tyrosine-deficient conditions. In addition, this study first documents mTORC1 inactivation and autophagy induction in PKU patients with BH₄ deficiency.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
authors.forename: Sang Su
authors.initials: SS
authors.lastname: Kwak
authors.forename: Jinkyu
authors.initials: J
authors.lastname: Suk
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Choi
authors.forename: Seungkyung
authors.initials: S
authors.lastname: Yang
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Seonghyang
authors.initials: S
authors.lastname: Sohn
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Chung
authors.forename: Yong Hee
authors.initials: YH
authors.lastname: Hong
authors.forename: Dong Hwan
authors.initials: DH
authors.lastname: Lee
authors.forename: Jeong Keun
authors.initials: JK
authors.lastname: Ahn
authors.forename: Hyesun
authors.initials: H
authors.lastname: Min
authors.forename: Ya-Min
authors.initials: YM
authors.lastname: Fu
authors.forename: Gary G
authors.initials: GG
authors.lastname: Meadows
authors.forename: Cheol O
authors.initials: CO
authors.lastname: Joe
mesh_terms: D000429:Alcohol Oxidoreductases / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001708:Biopterins / Q000031:analogs & derivatives* / Q000172:deficiency / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D007223:Infant; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes; D041681:NIH 3T3 Cells; D009479:Neuropeptides / Q000378:metabolism; D010649:Phenylalanine / Q000378:metabolism; D010651:Phenylalanine Hydroxylase / Q000378:metabolism; D010661:Phenylketonurias / Q000188:drug therapy / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; D014443:Tyrosine / Q000172:deficiency / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D001708:Biopterins; D014443:Tyrosine; D010649:Phenylalanine; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D010651:Phenylalanine Hydroxylase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; C003402:sapropterin