Author:
Xie Yajun,Lv Xiaoyan,Ni Dongsheng,Liu Jianing,Hu Yanxia,Liu Yamin,Liu Yunhong,Liu Rui,Zhao Hui,Lu Zhimin,Zhou Qin
Abstract
AbstractDecreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. Conversely, deficiency or depletion of TTC36 results in enhanced STK33-mediated HPD T382 phosphorylation and binding of PELI1 to HPD and subsequent PELI1-mediated HPD downregulation.Ttc36−/−mice have reduced HPD expression in the liver and exhibit tyrosinemia, damage to hippocampal neurons, and deficits of learning and memory. These findings reveal a previously unknown regulation of HPD expression and highlight the physiological significance of TTC36-STK33-PELI1-regulated HPD expression in tyrosinemia and tyrosinemia-associated neurological disorders.
Funder
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference38 articles.
1. Graham, J. Textbook of pediatric emergency medicinee, 6th Edition. Ann. Emerg. Med. 57, 707–707 (2011).
2. Endo, F., Katoh, H., Yamamoto, S. & Matsuda, I. A murine model for type III tyrosinemia: lack of immunologically detectable 4-hydroxyphenylpyruvic acid dioxygenase enzyme protein in a novel mouse strain with hypertyrosinemia. Am. J. Hum. Genet. 48, 704–709 (1991).
3. Hager, S. E., Gregerman, R. I. & Knox, W. E. p-Hydroxyphenylpyruvate oxidase of liver. J. Biol. Chem. 225, 935–947 (1957).
4. Nakai, C., Nozaki, M. & Hayaishi, O. Studies on a possible reaction intermediate of p-hydroxyphenylpyruvate dioxygenase. Biochem. Biophys. Res. Commun. 67, 590–595 (1975).
5. Endo, F. et al. Four-hydroxyphenylpyruvic acid oxidase deficiency with normal fumarylacetoacetase: a new variant form of hereditary hypertyrosinemia. Pediatr. Res. 17, 92–96 (1983).
Cited by
24 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献