2. Academic Validation
  3. 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

  • Nat Commun. 2019 Sep 19;10(1):4266. doi: 10.1038/s41467-019-12011-0.
Yajun Xie 1,  Xiaoyan Lv 2,  Dongsheng Ni 1,  Jianing Liu 1,  Yanxia Hu 1,  Yamin Liu 1,  Yunhong Liu 3,  Rui Liu 4,  Hui Zhao 5,  Zhimin Lu 6,  Qin Zhou 7
Affiliations

Affiliations

  • 1 The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, 400016, Chongqing, China.
  • 2 Department of Dermatology, West China Hospital, West China School of Medicine, Sichuan University, 610041, Chengdu, China.
  • 3 Clinical Laboratory, The People's Hospital of Longhua, 518109, Shenzhen, China.
  • 4 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, China.
  • 5 Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
  • 6 Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China. zhiminlu@zju.edu.cn.
  • 7 The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, 400016, Chongqing, China. zhouqin@cqmu.edu.cn.
PMID: 31537781 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.

Figures
Products