2. Academic Validation
  3. E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A

E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A

  • EMBO J. 2025 Feb;44(4):1249-1273. doi: 10.1038/s44318-024-00351-7.
Xiaoyan Hao # 1,  Zhengwei Hu # 1,  Mengjie Li 1,  Shuo Zhang 1,  Mibo Tang 1,  Chenwei Hao 1,  Shasha Qi 1,  Yuanyuan Liang 1,  Michael F Almeida 2,  Kaitlan Smith 2,  Chunyan Zuo 1,  Yanmei Feng 1,  Mengnan Guo 1,  Dongrui Ma 1,  Shuangjie Li 1,  Zhiyun Wang 1,  Yuemeng Sun 1,  Zhifen Deng 1,  Chengyuan Mao 1 3 4 5,  Zongping Xia 1,  Yong Jiang 6 7 8,  Yanxia Gao 6 7 8 9,  Yuming Xu 10 11 12 13,  Jonathan C Schisler 14,  Changhe Shi 15 16 17 18 19
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
  • 2 McAllister Heart Institute and the Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 3 Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450000, Henan, China.
  • 4 Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
  • 5 NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
  • 6 State Key Laboratory of Antiviral Drugs, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450000, China.
  • 7 Henan Key Laboratory of Critical Care Medicine, Department of Emergency Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450000, China.
  • 8 Institute of Infection and Immunity, Henan Academy of Innovations in Medical Science, Zhengzhou, 450000, China.
  • 9 Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Medical Key Laboratory of Poisoning Diseases of Henan Province, Zhengzhou, China.
  • 10 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. xuyuming@zzu.edu.cn.
  • 11 Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450000, Henan, China. xuyuming@zzu.edu.cn.
  • 12 Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. xuyuming@zzu.edu.cn.
  • 13 NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. xuyuming@zzu.edu.cn.
  • 14 McAllister Heart Institute and the Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. schisler@unc.edu.
  • 15 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
  • 16 Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
  • 17 Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
  • 18 NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
  • 19 Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China. shichanghe@zzu.edu.cn.
  • # Contributed equally.
PMID: 39806097 DOI: 10.1038/s44318-024-00351-7
Abstract

The carboxyl terminus of Hsc70-interacting protein (CHIP) is pivotal for managing misfolded and aggregated proteins via chaperone networks and degradation pathways. In a preclinical rodent model of CHIP-related ataxia, we observed that CHIP mutations lead to increased levels of phosphodiesterase 9A (PDE9A), whose role in this context remains poorly understood. Here, we investigated the molecular mechanisms underlying the role of PDE9A in CHIP-related ataxia and demonstrated that CHIP binds to PDE9A, facilitating its polyubiquitination and autophagic degradation. Conversely, dysfunctional CHIP disrupts this process, resulting in PDE9A accumulation, increased cGMP hydrolysis, and impaired PKG phosphorylation of CHIP at serine 19. This cascade further amplifies PDE9A accumulation, ultimately disrupting Mitophagy and triggering neuronal Apoptosis. Elevated PKA levels inhibit PDE9A degradation, further exacerbating this neuronal dysfunction. Notably, pharmacological inhibition of PDE9A via Bay 73-6691 or virus-mediated CHIP expression restored the balance of cGMP/cAMP signalling. These interventions protect against cerebellar neuropathologies, particularly Purkinje neuron Mitophagy dysfunction. Thus, PDE9A upregulation considerably exacerbates ataxia associated with CHIP mutations, and targeting the interaction between PDE9A and CHIP is an innovative therapeutic strategy for CHIP-related ataxia.

Keywords

CHIP; PDE9A; Ubiquitin-lysosome Pathway; cGMP-cAMP Signalling Crosstalk.

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