HPD degradation regulated by the TTC36-STK33-PELI1 signaling axis induces tyrosinemia and neurological damage

Yajun Xie,Hui Zhao,Zhimin Lu,Rui Liu,Yunhong Liu,Yanxia Hu,Yamin Liu,Xiaoyan Lv,Qin Zhou,Jianing Liu,Dongsheng Ni

doi:10.1038/s41467-019-12011-0

Abstract

Decreased 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.

Highlights

Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia
We demonstrate that molecular chaperone tetratricopeptide repeat domain 36 (TTC36) binds to HPD and blocks serine/threonine kinase 33 (STK33)-mediated T382 phosphorylation of HPD, thereby preventing the binding of FHA domain-containing PELI1 to HPD and subsequent HPD polyubiquitylation and degradation
STK33-enhanced T382 phosphorylation and polyubiquitylation of HPD were blocked by overexpression of TTC36 (Fig. 4i). These results indicate that STK33 phosphorylates HPD at T382 for HPD polyubiquitylation and that TTC36 expression reduces the binding of STK33 to HPD, leading to inhibited HPD polyubiquitylation and degradation

Summary

Introduction

Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. 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 tyrosinemiaassociated neurological disorders. Tyrosinemia type III patients with homozygous missense mutation of Hpd and HPD deficiency suffer from neurological abnormalities[9,10] These reports indicate a critical role of HPD in hypertyrosinemia, the mechanism underlying the regulation of HPD expression is unclear. Knockout of Ttc[36] in mice reduces HPD expression in liver and leads to tyrosinemia phenotypes with neuropathological changes and impaired learning and memory

Methods

Results

Conclusion