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

Yajun Xie, Xiaoyan Lv, Dongsheng Ni, Jianing Liu, Yanxia Hu, Yamin Liu, Yunhong Liu, Rui Liu, Hui Zhao, Zhimin Lu () and Qin Zhou ()
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Yajun Xie: Chongqing Medical University
Xiaoyan Lv: Sichuan University
Dongsheng Ni: Chongqing Medical University
Jianing Liu: Chongqing Medical University
Yanxia Hu: Chongqing Medical University
Yamin Liu: Chongqing Medical University
Yunhong Liu: The People’s Hospital of Longhua
Rui Liu: Sichuan University
Hui Zhao: The Chinese University of Hong Kong
Zhimin Lu: Zhejiang University School of Medicine
Qin Zhou: Chongqing Medical University

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12011-0

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