2. Academic Validation
  3. Regulation of primary cilia disassembly through HUWE1-mediated TTBK2 degradation plays a crucial role in cerebellar development and medulloblastoma growth

Regulation of primary cilia disassembly through HUWE1-mediated TTBK2 degradation plays a crucial role in cerebellar development and medulloblastoma growth

  • Cell Death Differ. 2024 Oct;31(10):1349-1361. doi: 10.1038/s41418-024-01325-2.
I-Hsuan Lin 1 2,  Yue-Ru Li 3,  Chia-Hsiang Chang 3,  Yu-Wen Cheng 2,  Yu-Ting Wang 4 5,  Yu-Shuen Tsai 6,  Pei-Yi Lin 4 5,  Chien-Han Kao 2,  Ting-Yu Su 2,  Chih-Sin Hsu 6,  Chien-Yi Tung 6,  Pang-Hung Hsu 7,  Olivier Ayrault 8 9,  Bon-Chu Chung 4 10,  Jin-Wu Tsai 11 12 13 14,  Won-Jing Wang 15 16 17
Affiliations

Affiliations

  • 1 Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan.
  • 2 Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
  • 3 Institute of Brain Science, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
  • 4 Institute of Molecular Biology, Academia Sinica, Taipei, 115, Taiwan.
  • 5 Department of Life Sciences, National Central University, Taoyuan, 300, Taiwan.
  • 6 Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
  • 7 Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, 202, Taiwan.
  • 8 Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France.
  • 9 Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U, Orsay, France.
  • 10 Graduate Institute of Biomedical Sciences, Neuroscience and Brain Disease Center, China Medical University, Taichung, 404, Taiwan.
  • 11 Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan. tsaijw@nycu.edu.tw.
  • 12 Institute of Brain Science, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. tsaijw@nycu.edu.tw.
  • 13 Advanced Therapeutics Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. tsaijw@nycu.edu.tw.
  • 14 Brain Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. tsaijw@nycu.edu.tw.
  • 15 Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan. wangwj@nycu.edu.tw.
  • 16 Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. wangwj@nycu.edu.tw.
  • 17 Advanced Therapeutics Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. wangwj@nycu.edu.tw.
PMID: 38879724 DOI: 10.1038/s41418-024-01325-2
Abstract

Development of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to support GNP proliferation, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. Here, we establish the pivotal roles for the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and the E3 ubiquitin Ligase HUWE1 in GNP proliferation. We show that TTBK2 is highly expressed in proliferating GNPs under Sonic Hedgehog (SHH) signaling, coinciding with active GNP proliferation and the presence of primary cilia. TTBK2 stabilizes primary cilia by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. Mechanistically, we identify HUWE1 as a novel centrosomal E3 Ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. Disassembly of primary cilia serves as a trigger for GNP differentiation, allowing their migration from the external granule layer (EGL) of the cerebellum to the internal granule layer (IGL) for subsequent maturation. Moreover, we have established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this Cancer type. In summary, our findings reveal the mechanism governing cerebellar development and highlight a potential anti-cancer strategy for SHH-MB.

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