Open Access

Targeted disruption of GAK stagnates autophagic flux by disturbing lysosomal dynamics

  • Authors:
    • Masaya Miyazaki
    • Masaki Hiramoto
    • Naoharu Takano
    • Hiroko Kokuba
    • Jun Takemura
    • Mayumi Tokuhisa
    • Hirotsugu Hino
    • Hiromi Kazama
    • Keisuke Miyazawa
  • View Affiliations

  • Published online on: August 30, 2021     https://doi.org/10.3892/ijmm.2021.5028
  • Article Number: 195
  • Copyright: © Miyazaki et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The autophagy‑lysosome system allows cells to adapt to environmental changes by regulating the degradation and recycling of cellular components, and to maintain homeostasis by removing aggregated proteins and defective organelles. Cyclin G‑associated kinase (GAK) is involved in the regulation of clathrin‑dependent endocytosis and cell cycle progression. In addition, a single nucleotide polymorphism at the GAK locus has been reported as a risk factor for Parkinson's disease. However, the roles of GAK in the autophagy‑lysosome system are not completely understood, thus the present study aimed to clarify this. In the present study, under genetic disruption or chemical inhibition of GAK, analyzing autophagic flux and observing morphological changes of autophagosomes and autolysosomes revealed that GAK controlled lysosomal dynamics via actomyosin regulation, resulting in a steady progression of autophagy. GAK knockout (KO) in A549 cells impaired autophagosome‑lysosome fusion and autophagic lysosome reformation, which resulted in the accumulation of enlarged autophagosomes and autolysosomes during prolonged starvation. The stagnation of autophagic flux accompanied by these phenomena was also observed with the addition of a GAK inhibitor. Furthermore, the addition of Rho‑associated protein kinase (ROCK) inhibitor or ROCK1 knockdown mitigated GAK KO‑mediated effects. The results suggested a vital role of GAK in controlling lysosomal dynamics via maintaining lysosomal homeostasis during autophagy.
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October-2021
Volume 48 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Miyazaki M, Hiramoto M, Takano N, Kokuba H, Takemura J, Tokuhisa M, Hino H, Kazama H and Miyazawa K: Targeted disruption of GAK stagnates autophagic flux by disturbing lysosomal dynamics. Int J Mol Med 48: 195, 2021
APA
Miyazaki, M., Hiramoto, M., Takano, N., Kokuba, H., Takemura, J., Tokuhisa, M. ... Miyazawa, K. (2021). Targeted disruption of GAK stagnates autophagic flux by disturbing lysosomal dynamics. International Journal of Molecular Medicine, 48, 195. https://doi.org/10.3892/ijmm.2021.5028
MLA
Miyazaki, M., Hiramoto, M., Takano, N., Kokuba, H., Takemura, J., Tokuhisa, M., Hino, H., Kazama, H., Miyazawa, K."Targeted disruption of GAK stagnates autophagic flux by disturbing lysosomal dynamics". International Journal of Molecular Medicine 48.4 (2021): 195.
Chicago
Miyazaki, M., Hiramoto, M., Takano, N., Kokuba, H., Takemura, J., Tokuhisa, M., Hino, H., Kazama, H., Miyazawa, K."Targeted disruption of GAK stagnates autophagic flux by disturbing lysosomal dynamics". International Journal of Molecular Medicine 48, no. 4 (2021): 195. https://doi.org/10.3892/ijmm.2021.5028