1. Academic Validation
  2. Chlorpromazine affects autophagy in association with altered Rag GTPase-mTORC1-TFEB signaling

Chlorpromazine affects autophagy in association with altered Rag GTPase-mTORC1-TFEB signaling

  • Front Cell Dev Biol. 2023 Sep 8:11:1266198. doi: 10.3389/fcell.2023.1266198.
Ningning Li 1 Lingling Rao 1 Xueqing Zhao 1 Junwen Shen 1 Dan Su 1 Guoqiang Ma 1 Shan Sun 1 2 Qilian Ma 1 3 Li Zhang 4 Chunsheng Dong 5 Kin Yip Tam 2 Jochen H M Prehn 3 Hongfeng Wang 1 Zheng Ying 1
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
  • 2 Faculty of Health Sciences, University of Macau, Taipa, China.
  • 3 Department of Physiology and Medical Physics and Future-Neuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
  • 4 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, China.
  • 5 Institutes of Biology and Medical Science, Soochow University, Suzhou, China.
Abstract

Autophagy is a critical protein and organelle quality control system, which regulates cellular homeostasis and survival. Growing pieces of evidence suggest that autophagic dysfunction is strongly associated with many human diseases, including neurological diseases and Cancer. Among various autophagic regulators, microphthalmia (MiT)/TFE transcription factors, including transcription factor EB (TFEB), have been shown to act as the master regulators of autophagosome and lysosome biogenesis in both physiological and pathological conditions. According to the previous studies, chlorpromazine (CPZ), an FDA-approved antipsychotic drug, affects Autophagy in diverse cell lines, but the underlying mechanism remains elusive. In our present study, we find that CPZ treatment induces TFEB nuclear translocation through Rag GTPases, the upstream regulators of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Meanwhile, CPZ treatment also blocks autophagosome-lysosome fusion. Notably, we find a significant accumulation of immature autophagosome vesicles in CPZ-treated cells, which may impede cellular homeostasis due to the dysfunction of the autophagy-lysosome pathway. Interestingly and importantly, our data suggest that the expression of the active form of Rag GTPase heterodimers helps in reducing the accumulation of autophagosomes in CPZ-treated cells, further suggesting a major contribution of the Rag GTPase-mTORC1-TFEB signaling axis in CPZ-induced autophagic impairment.

Keywords

CPZ; Rag GTPases; TFEB; autophagy; mTORC1.

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