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Cerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1

Author

Listed:
  • Yalan Zhang

    (Yale University School of Medicine)

  • Luis Varela

    (Yale University School of Medicine)

  • Klara Szigeti-Buck

    (Yale University School of Medicine)

  • Adam Williams

    (Yale University School of Medicine
    The Jackson Laboratory)

  • Milan Stoiljkovic

    (Yale University School of Medicine)

  • Matija Šestan-Peša

    (Yale University School of Medicine)

  • Jorge Henao-Mejia

    (Yale University School of Medicine
    University of Pennsylvania, Children’s Hospital of Philadelphia)

  • Pasquale D’Acunzo

    (The Nathan S. Kline Institute for Psychiatric Research
    New York University School of Medicine)

  • Efrat Levy

    (The Nathan S. Kline Institute for Psychiatric Research
    New York University School of Medicine
    New York University School of Medicine
    New York University School of Medicine)

  • Richard A. Flavell

    (Yale University School of Medicine
    Howard Hughes Medical Institute)

  • Tamas L. Horvath

    (Yale University School of Medicine)

  • Leonard K. Kaczmarek

    (Yale University School of Medicine
    Yale School of Medicine)

Abstract

Mutations in KCNC3, which encodes the Kv3.3 potassium channel, cause degeneration of the cerebellum, but exactly how the activity of an ion channel is linked to the survival of cerebellar neurons is not understood. Here, we report that Kv3.3 channels bind and stimulate Tank Binding Kinase 1 (TBK1), an enzyme that controls trafficking of membrane proteins into multivesicular bodies, and that this stimulation is greatly increased by a disease-causing Kv3.3 mutation. TBK1 activity is required for the binding of Kv3.3 to its auxiliary subunit Hax-1, which prevents channel inactivation with depolarization. Hax-1 is also an anti-apoptotic protein required for survival of cerebellar neurons. Overactivation of TBK1 by the mutant channel leads to the loss of Hax-1 by its accumulation in multivesicular bodies and lysosomes, and also stimulates exosome release from neurons. This process is coupled to activation of caspases and increased cell death. Our studies indicate that Kv3.3 channels are directly coupled to TBK1-dependent biochemical pathways that determine the trafficking of cellular constituents and neuronal survival.

Suggested Citation

  • Yalan Zhang & Luis Varela & Klara Szigeti-Buck & Adam Williams & Milan Stoiljkovic & Matija Šestan-Peša & Jorge Henao-Mejia & Pasquale D’Acunzo & Efrat Levy & Richard A. Flavell & Tamas L. Horvath & L, 2021. "Cerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22003-8
    DOI: 10.1038/s41467-021-22003-8
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    1. Huilin Jin & Xiaoling Huang & Qihao Pan & Ning Ma & Xiaoshan Xie & Yue Wei & Fenghai Yu & Weijie Wen & Boyu Zhang & Peng Zhang & Xijie Chen & Jie Wang & Ran-yi Liu & Junzhong Lin & Xiangqi Meng & Mong, 2024. "The EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Shiyu Dai & Yuan-Qin Min & Qi Li & Kuan Feng & Zhenyu Jiang & Zhiying Wang & Cunhuan Zhang & Fuli Ren & Yaohui Fang & Jingyuan Zhang & Qiong Zhu & Manli Wang & Hualin Wang & Fei Deng & Yun-Jia Ning, 2023. "Interactome profiling of Crimean-Congo hemorrhagic fever virus glycoproteins," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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