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

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 autophagi...

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Autores principales: Li, Ningning, Rao, Lingling, Zhao, Xueqing, Shen, Junwen, Su, Dan, Ma, Guoqiang, Sun, Shan, Ma, Qilian, Zhang, Li, Dong, Chunsheng, Tam, Kin Yip, Prehn, Jochen H. M., Wang, Hongfeng, Ying, Zheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10514517/
https://www.ncbi.nlm.nih.gov/pubmed/37745295
http://dx.doi.org/10.3389/fcell.2023.1266198
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author Li, Ningning
Rao, Lingling
Zhao, Xueqing
Shen, Junwen
Su, Dan
Ma, Guoqiang
Sun, Shan
Ma, Qilian
Zhang, Li
Dong, Chunsheng
Tam, Kin Yip
Prehn, Jochen H. M.
Wang, Hongfeng
Ying, Zheng
author_facet Li, Ningning
Rao, Lingling
Zhao, Xueqing
Shen, Junwen
Su, Dan
Ma, Guoqiang
Sun, Shan
Ma, Qilian
Zhang, Li
Dong, Chunsheng
Tam, Kin Yip
Prehn, Jochen H. M.
Wang, Hongfeng
Ying, Zheng
author_sort Li, Ningning
collection PubMed
description 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.
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spelling pubmed-105145172023-09-23 Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling Li, Ningning Rao, Lingling Zhao, Xueqing Shen, Junwen Su, Dan Ma, Guoqiang Sun, Shan Ma, Qilian Zhang, Li Dong, Chunsheng Tam, Kin Yip Prehn, Jochen H. M. Wang, Hongfeng Ying, Zheng Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2023-09-08 /pmc/articles/PMC10514517/ /pubmed/37745295 http://dx.doi.org/10.3389/fcell.2023.1266198 Text en Copyright © 2023 Li, Rao, Zhao, Shen, Su, Ma, Sun, Ma, Zhang, Dong, Tam, Prehn, Wang and Ying. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Li, Ningning
Rao, Lingling
Zhao, Xueqing
Shen, Junwen
Su, Dan
Ma, Guoqiang
Sun, Shan
Ma, Qilian
Zhang, Li
Dong, Chunsheng
Tam, Kin Yip
Prehn, Jochen H. M.
Wang, Hongfeng
Ying, Zheng
Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling
title Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling
title_full Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling
title_fullStr Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling
title_full_unstemmed Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling
title_short Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling
title_sort chlorpromazine affects autophagy in association with altered rag gtpase–mtorc1–tfeb signaling
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10514517/
https://www.ncbi.nlm.nih.gov/pubmed/37745295
http://dx.doi.org/10.3389/fcell.2023.1266198
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