HPD degradation regulated by the TTC36-STK33-PELI1 signaling axis induces tyrosinemia and neurological damage
HPD degradation regulated by the TTC36-STK33-PELI1 signaling axis induces tyrosinemia and neurological damage
复制标题
TTC36-STK33-PELI1 信号轴调节的 HPD 降解可诱导酪氨酸血症和神经损伤
DOI：
10.1038/s41467-019-12011-0
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发表时间：
2019-09-19
影响因子：
16.6
通讯作者：
Zhou, Qin
中科院分区：
文献类型：
--
作者：
Xie, Yajun;Lv, Xiaoyan;Zhou, Qin
4-羟基苯基丙酮酸双加氧酶（HPD）是酪氨酸代谢的关键酶，其表达降低是导致人酪氨酸血症的原因之一。然而，HPD表达的调控在很大程度上仍然未知。在这里，我们证明了在肝脏中高表达的分子伴侣TTC36与HPD相关，并减少蛋白激酶STK33与HPD的结合，从而抑制STK33介导的HPD T382磷酸化。HPD T382磷酸化的降低导致含有FHA结构域的PELI1的募集和PELI1介导的HPD多泛素化和降解受损。相反，TTC36缺乏或缺失导致stk33介导的HPD T382磷酸化增强，PELI1与HPD结合，随后PELI1介导的HPD下调。Ttc36（-/-）小鼠肝脏HPD表达降低，表现为酪氨酸血症，海马神经元损伤，学习和记忆障碍。这些发现揭示了以前未知的HPD表达调控，并强调了ttc36 - stk33 - peli1调控的HPD表达在酪氨酸血症和酪氨酸血症相关神经系统疾病中的生理意义。
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.