Suppression of lysosome function induces autophagy via a feedback down-regulation of MTOR complex 1 (MTORC1) activity

Min Li, Bilon Khambu, Hao Zhang, Jeong Han Kang, Xiaoyun Chen, Daohong Chen, Laura Vollmer, Pei Qing Liu, Andreas Vogt, Xiao-Ming Yin

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Autophagy can be activated via MTORC1 down-regulation by amino acid deprivation and by certain chemicals such as rapamycin, torin, and niclosamide. Lysosome is the degrading machine for autophagy but has also been linked to MTORC1 activation through the Rag/RRAG GTPase pathway. This association raises the question of whether lysosome can be involved in the initiation of autophagy. Toward this end, we found that niclosamide, an MTORC1 inhibitor, was able to inhibit lysosome degradation and increase lysosomal permeability. Niclosamide was ineffective in inhibiting MTORC1 in cells expressing constitutively activated Rag proteins, suggesting that its inhibitory effects were targeted to the Rag-MTORC1 signaling system. This places niclosamide in the same category of bafilomycin A1 and concanamycin A, inhibitors of the vacuolar H +-ATPase, for its dependence on Rag GTPase in suppression of MTORC1. Surprisingly, classical lysosome inhibitors such as chloroquine, E64D, and pepstatin A were also able to inhibit MTORC1 in a Rag-dependent manner. These lysosome inhibitors were able to activate early autophagy events represented by ATG16L1 and ATG12 puncta formation. Our work established a link between the functional status of the lysosome in general to the Rag-MTORC1 signaling axis and autophagy activation. Thus, the lysosome is not only required for autophagic degradation but also affects autophagy activation. Lysosome inhibitors can have a dual effect in suppressing autophagy degradation and in initiating autophagy.

Original languageEnglish
Pages (from-to)35769-35780
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number50
DOIs
StatePublished - Dec 13 2013

Fingerprint

Niclosamide
Autophagy
Lysosomes
Down-Regulation
Feedback
GTP Phosphohydrolases
Chemical activation
Corrosion inhibitors
Degradation
Vacuolar Proton-Translocating ATPases
Chloroquine
Sirolimus
Cells
Association reactions
Amino Acids
Permeability
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Suppression of lysosome function induces autophagy via a feedback down-regulation of MTOR complex 1 (MTORC1) activity. / Li, Min; Khambu, Bilon; Zhang, Hao; Kang, Jeong Han; Chen, Xiaoyun; Chen, Daohong; Vollmer, Laura; Liu, Pei Qing; Vogt, Andreas; Yin, Xiao-Ming.

In: Journal of Biological Chemistry, Vol. 288, No. 50, 13.12.2013, p. 35769-35780.

Research output: Contribution to journalArticle

Li, M, Khambu, B, Zhang, H, Kang, JH, Chen, X, Chen, D, Vollmer, L, Liu, PQ, Vogt, A & Yin, X-M 2013, 'Suppression of lysosome function induces autophagy via a feedback down-regulation of MTOR complex 1 (MTORC1) activity', Journal of Biological Chemistry, vol. 288, no. 50, pp. 35769-35780. https://doi.org/10.1074/jbc.M113.511212
Li, Min ; Khambu, Bilon ; Zhang, Hao ; Kang, Jeong Han ; Chen, Xiaoyun ; Chen, Daohong ; Vollmer, Laura ; Liu, Pei Qing ; Vogt, Andreas ; Yin, Xiao-Ming. / Suppression of lysosome function induces autophagy via a feedback down-regulation of MTOR complex 1 (MTORC1) activity. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 50. pp. 35769-35780.
@article{10b00237f40747e2b00546ffded7282f,
title = "Suppression of lysosome function induces autophagy via a feedback down-regulation of MTOR complex 1 (MTORC1) activity",
abstract = "Autophagy can be activated via MTORC1 down-regulation by amino acid deprivation and by certain chemicals such as rapamycin, torin, and niclosamide. Lysosome is the degrading machine for autophagy but has also been linked to MTORC1 activation through the Rag/RRAG GTPase pathway. This association raises the question of whether lysosome can be involved in the initiation of autophagy. Toward this end, we found that niclosamide, an MTORC1 inhibitor, was able to inhibit lysosome degradation and increase lysosomal permeability. Niclosamide was ineffective in inhibiting MTORC1 in cells expressing constitutively activated Rag proteins, suggesting that its inhibitory effects were targeted to the Rag-MTORC1 signaling system. This places niclosamide in the same category of bafilomycin A1 and concanamycin A, inhibitors of the vacuolar H +-ATPase, for its dependence on Rag GTPase in suppression of MTORC1. Surprisingly, classical lysosome inhibitors such as chloroquine, E64D, and pepstatin A were also able to inhibit MTORC1 in a Rag-dependent manner. These lysosome inhibitors were able to activate early autophagy events represented by ATG16L1 and ATG12 puncta formation. Our work established a link between the functional status of the lysosome in general to the Rag-MTORC1 signaling axis and autophagy activation. Thus, the lysosome is not only required for autophagic degradation but also affects autophagy activation. Lysosome inhibitors can have a dual effect in suppressing autophagy degradation and in initiating autophagy.",
author = "Min Li and Bilon Khambu and Hao Zhang and Kang, {Jeong Han} and Xiaoyun Chen and Daohong Chen and Laura Vollmer and Liu, {Pei Qing} and Andreas Vogt and Xiao-Ming Yin",
year = "2013",
month = "12",
day = "13",
doi = "10.1074/jbc.M113.511212",
language = "English",
volume = "288",
pages = "35769--35780",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "50",

}

TY - JOUR

T1 - Suppression of lysosome function induces autophagy via a feedback down-regulation of MTOR complex 1 (MTORC1) activity

AU - Li, Min

AU - Khambu, Bilon

AU - Zhang, Hao

AU - Kang, Jeong Han

AU - Chen, Xiaoyun

AU - Chen, Daohong

AU - Vollmer, Laura

AU - Liu, Pei Qing

AU - Vogt, Andreas

AU - Yin, Xiao-Ming

PY - 2013/12/13

Y1 - 2013/12/13

N2 - Autophagy can be activated via MTORC1 down-regulation by amino acid deprivation and by certain chemicals such as rapamycin, torin, and niclosamide. Lysosome is the degrading machine for autophagy but has also been linked to MTORC1 activation through the Rag/RRAG GTPase pathway. This association raises the question of whether lysosome can be involved in the initiation of autophagy. Toward this end, we found that niclosamide, an MTORC1 inhibitor, was able to inhibit lysosome degradation and increase lysosomal permeability. Niclosamide was ineffective in inhibiting MTORC1 in cells expressing constitutively activated Rag proteins, suggesting that its inhibitory effects were targeted to the Rag-MTORC1 signaling system. This places niclosamide in the same category of bafilomycin A1 and concanamycin A, inhibitors of the vacuolar H +-ATPase, for its dependence on Rag GTPase in suppression of MTORC1. Surprisingly, classical lysosome inhibitors such as chloroquine, E64D, and pepstatin A were also able to inhibit MTORC1 in a Rag-dependent manner. These lysosome inhibitors were able to activate early autophagy events represented by ATG16L1 and ATG12 puncta formation. Our work established a link between the functional status of the lysosome in general to the Rag-MTORC1 signaling axis and autophagy activation. Thus, the lysosome is not only required for autophagic degradation but also affects autophagy activation. Lysosome inhibitors can have a dual effect in suppressing autophagy degradation and in initiating autophagy.

AB - Autophagy can be activated via MTORC1 down-regulation by amino acid deprivation and by certain chemicals such as rapamycin, torin, and niclosamide. Lysosome is the degrading machine for autophagy but has also been linked to MTORC1 activation through the Rag/RRAG GTPase pathway. This association raises the question of whether lysosome can be involved in the initiation of autophagy. Toward this end, we found that niclosamide, an MTORC1 inhibitor, was able to inhibit lysosome degradation and increase lysosomal permeability. Niclosamide was ineffective in inhibiting MTORC1 in cells expressing constitutively activated Rag proteins, suggesting that its inhibitory effects were targeted to the Rag-MTORC1 signaling system. This places niclosamide in the same category of bafilomycin A1 and concanamycin A, inhibitors of the vacuolar H +-ATPase, for its dependence on Rag GTPase in suppression of MTORC1. Surprisingly, classical lysosome inhibitors such as chloroquine, E64D, and pepstatin A were also able to inhibit MTORC1 in a Rag-dependent manner. These lysosome inhibitors were able to activate early autophagy events represented by ATG16L1 and ATG12 puncta formation. Our work established a link between the functional status of the lysosome in general to the Rag-MTORC1 signaling axis and autophagy activation. Thus, the lysosome is not only required for autophagic degradation but also affects autophagy activation. Lysosome inhibitors can have a dual effect in suppressing autophagy degradation and in initiating autophagy.

UR - http://www.scopus.com/inward/record.url?scp=84890405966&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890405966&partnerID=8YFLogxK

U2 - 10.1074/jbc.M113.511212

DO - 10.1074/jbc.M113.511212

M3 - Article

C2 - 24174532

AN - SCOPUS:84890405966

VL - 288

SP - 35769

EP - 35780

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 50

ER -