A negative feedback regulation of MTORC1 activity by the lysosomal Ca2+ channel MCOLN1 (mucolipin 1) using a CALM (calmodulin)-dependent mechanism

Xue Sun; Yiming Yang; Xi Zoë Zhong; Qi Cao; Xin Hong Zhu; Xiaojuan Zhu; Xian Ping Dong

doi:10.1080/15548627.2017.1389822

A negative feedback regulation of MTORC1 activity by the lysosomal Ca²⁺ channel MCOLN1 (mucolipin 1) using a CALM (calmodulin)-dependent mechanism

Xue Sun, Yiming Yang, Xi Zoë Zhong, Qi Cao, Xin Hong Zhu, Xiaojuan Zhu, Xian Ping Dong

Medicine

Research output: Contribution to journal › Article › peer-review

72 Citations (Scopus)

Abstract

Macroautophagy/autophagy is an evolutionarily conserved pathway that is required for cellular homeostasis, growth and survival. The lysosome plays an essential role in autophagy regulation. For example, the activity of MTORC1, a master regulator of autophagy, is regulated by nutrients within the lysosome. Starvation inhibits MTORC1 causing autophagy induction. Given that MTORC1 is critical for protein synthesis and cellular homeostasis, a feedback regulatory mechanism must exist to restore MTORC1 during starvation. However, the molecular mechanism underlying this feedback regulation is unclear. In this study, we report that starvation activates the lysosomal Ca²⁺ release channel MCOLN1 (mucolipin 1) by relieving MTORC1's inhibition of the channel. Activated MCOLN1 in turn facilitates MTORC1 activity that requires CALM (calmodulin). Moreover, both MCOLN1 and CALM are necessary for MTORC1 reactivation during prolonged starvation. Our data suggest that lysosomal Ca²⁺ signaling is an essential component of the canonical MTORC1-dependent autophagy pathway and MCOLN1 provides a negative feedback regulation of MTORC1 to prevent excessive loss of MTORC1 function during starvation. The feedback regulation may be important for maintaining cellular homeostasis during starvation, as well as many other stressful or disease conditions.

Original language	English
Pages (from-to)	38-52
Number of pages	15
Journal	Autophagy
Volume	14
Issue number	1
DOIs	https://doi.org/10.1080/15548627.2017.1389822
Publication status	Published - Jan 2 2018

Bibliographical note

Funding Information:
This work was supported by the Government of Canada j Canadian Institutes of Health Research (CIHR) [grant number MOP-119349]; Canada Foundation for Innovation (CFI) [grant number 29291]; Nova Scotia Health Research Foundation (NSHRF) [grant number MED-PRO-2011-7485]; and the Program of International S and T Cooperation [grant number 2015DFA31580].

Funding Information:
This work was supported by the Government of Canada | Canadian Institutes of Health Research (CIHR) [grant number MOP-119349]; Canada Foundation for Innovation (CFI) [grant number 29291]; Nova Scotia Health Research Foundation (NSHRF) [grant number MED-PRO-2011-7485]; and the Program of International S and T Cooperation [grant number 2015DFA31580]. This work was supported by startup funds to X.D. from the Department of Physiology and Biophysics, Dalhousie University, DMRF Equipment Grant, DMRF new investigator award, CIHR grant (MOP-119349), CIHR New Investigator award (201109MSH-261462-208625), NSHRF Establishment Grant (MED-PRO-2011-7485), CFI Leaders Opportunity Fund-Funding for research infrastructure (29291), and the Program of International S and T Cooperation (2015DFA31580). We thank Lin Mei for the CALM plasmids, Michael X. Zhu for the LAMP1 plasmids, Mitsunori Fukuda for the SYT7-DN plasmid, Robert pbell for the GECO construct, Rob Onyenwoke for the human MCOLN1-EGFP, MCOLN1S51E-EGFP and MCOLN1S572E,S576E-EGFP, and Stephen Whitefield for his assistance in image analysis. We appreciate the encouragement and helpful comments from other members of the Dong laboratory.

Funding Information:
This work was supported by startup funds to X.D. from the Department of Physiology and Biophysics, Dalhousie University, DMRF Equipment Grant, DMRF new investigator award, CIHR grant (MOP-119349), CIHR New Investigator award (201109MSH-261462-208625), NSHRF Establishment Grant (MED-PRO-2011-7485), CFI Leaders Opportunity Fund-Funding for research infrastructure (29291), and the Program of International S and T Cooperation (2015DFA31580). We thank Lin Mei for the CALM plasmids, Michael X. Zhu for the LAMP1 plasmids, Mitsunori Fukuda for the SYT7-DN plasmid, Robert pbell for the GECO construct, Rob Onyenwoke for the human MCOLN1-EGFP, MCOLN1S51E-EGFP and MCOLN1S572E,S576E-EGFP, and Stephen Whitefield for his assistance in image analysis. We appreciate the encouragement and helpful comments from other members of the Dong laboratory.

Publisher Copyright:
© 2017 Taylor and Francis.

ASJC Scopus Subject Areas

Molecular Biology
Cell Biology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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10.1080/15548627.2017.1389822

Cite this

@article{6b18cbfb96284e55b459bec62f23f71c,

title = "A negative feedback regulation of MTORC1 activity by the lysosomal Ca2+ channel MCOLN1 (mucolipin 1) using a CALM (calmodulin)-dependent mechanism",

abstract = "Macroautophagy/autophagy is an evolutionarily conserved pathway that is required for cellular homeostasis, growth and survival. The lysosome plays an essential role in autophagy regulation. For example, the activity of MTORC1, a master regulator of autophagy, is regulated by nutrients within the lysosome. Starvation inhibits MTORC1 causing autophagy induction. Given that MTORC1 is critical for protein synthesis and cellular homeostasis, a feedback regulatory mechanism must exist to restore MTORC1 during starvation. However, the molecular mechanism underlying this feedback regulation is unclear. In this study, we report that starvation activates the lysosomal Ca2+ release channel MCOLN1 (mucolipin 1) by relieving MTORC1's inhibition of the channel. Activated MCOLN1 in turn facilitates MTORC1 activity that requires CALM (calmodulin). Moreover, both MCOLN1 and CALM are necessary for MTORC1 reactivation during prolonged starvation. Our data suggest that lysosomal Ca2+ signaling is an essential component of the canonical MTORC1-dependent autophagy pathway and MCOLN1 provides a negative feedback regulation of MTORC1 to prevent excessive loss of MTORC1 function during starvation. The feedback regulation may be important for maintaining cellular homeostasis during starvation, as well as many other stressful or disease conditions.",

author = "Xue Sun and Yiming Yang and Zhong, {Xi Zo{\"e}} and Qi Cao and Zhu, {Xin Hong} and Xiaojuan Zhu and Dong, {Xian Ping}",

note = "Funding Information: This work was supported by the Government of Canada j Canadian Institutes of Health Research (CIHR) [grant number MOP-119349]; Canada Foundation for Innovation (CFI) [grant number 29291]; Nova Scotia Health Research Foundation (NSHRF) [grant number MED-PRO-2011-7485]; and the Program of International S and T Cooperation [grant number 2015DFA31580]. Funding Information: This work was supported by the Government of Canada | Canadian Institutes of Health Research (CIHR) [grant number MOP-119349]; Canada Foundation for Innovation (CFI) [grant number 29291]; Nova Scotia Health Research Foundation (NSHRF) [grant number MED-PRO-2011-7485]; and the Program of International S and T Cooperation [grant number 2015DFA31580]. This work was supported by startup funds to X.D. from the Department of Physiology and Biophysics, Dalhousie University, DMRF Equipment Grant, DMRF new investigator award, CIHR grant (MOP-119349), CIHR New Investigator award (201109MSH-261462-208625), NSHRF Establishment Grant (MED-PRO-2011-7485), CFI Leaders Opportunity Fund-Funding for research infrastructure (29291), and the Program of International S and T Cooperation (2015DFA31580). We thank Lin Mei for the CALM plasmids, Michael X. Zhu for the LAMP1 plasmids, Mitsunori Fukuda for the SYT7-DN plasmid, Robert pbell for the GECO construct, Rob Onyenwoke for the human MCOLN1-EGFP, MCOLN1S51E-EGFP and MCOLN1S572E,S576E-EGFP, and Stephen Whitefield for his assistance in image analysis. We appreciate the encouragement and helpful comments from other members of the Dong laboratory. Funding Information: This work was supported by startup funds to X.D. from the Department of Physiology and Biophysics, Dalhousie University, DMRF Equipment Grant, DMRF new investigator award, CIHR grant (MOP-119349), CIHR New Investigator award (201109MSH-261462-208625), NSHRF Establishment Grant (MED-PRO-2011-7485), CFI Leaders Opportunity Fund-Funding for research infrastructure (29291), and the Program of International S and T Cooperation (2015DFA31580). We thank Lin Mei for the CALM plasmids, Michael X. Zhu for the LAMP1 plasmids, Mitsunori Fukuda for the SYT7-DN plasmid, Robert pbell for the GECO construct, Rob Onyenwoke for the human MCOLN1-EGFP, MCOLN1S51E-EGFP and MCOLN1S572E,S576E-EGFP, and Stephen Whitefield for his assistance in image analysis. We appreciate the encouragement and helpful comments from other members of the Dong laboratory. Publisher Copyright: {\textcopyright} 2017 Taylor and Francis.",

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doi = "10.1080/15548627.2017.1389822",

language = "English",

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T1 - A negative feedback regulation of MTORC1 activity by the lysosomal Ca2+ channel MCOLN1 (mucolipin 1) using a CALM (calmodulin)-dependent mechanism

AU - Sun, Xue

AU - Yang, Yiming

AU - Zhong, Xi Zoë

AU - Cao, Qi

AU - Zhu, Xin Hong

AU - Zhu, Xiaojuan

AU - Dong, Xian Ping

N1 - Funding Information: This work was supported by the Government of Canada j Canadian Institutes of Health Research (CIHR) [grant number MOP-119349]; Canada Foundation for Innovation (CFI) [grant number 29291]; Nova Scotia Health Research Foundation (NSHRF) [grant number MED-PRO-2011-7485]; and the Program of International S and T Cooperation [grant number 2015DFA31580]. Funding Information: This work was supported by the Government of Canada | Canadian Institutes of Health Research (CIHR) [grant number MOP-119349]; Canada Foundation for Innovation (CFI) [grant number 29291]; Nova Scotia Health Research Foundation (NSHRF) [grant number MED-PRO-2011-7485]; and the Program of International S and T Cooperation [grant number 2015DFA31580]. This work was supported by startup funds to X.D. from the Department of Physiology and Biophysics, Dalhousie University, DMRF Equipment Grant, DMRF new investigator award, CIHR grant (MOP-119349), CIHR New Investigator award (201109MSH-261462-208625), NSHRF Establishment Grant (MED-PRO-2011-7485), CFI Leaders Opportunity Fund-Funding for research infrastructure (29291), and the Program of International S and T Cooperation (2015DFA31580). We thank Lin Mei for the CALM plasmids, Michael X. Zhu for the LAMP1 plasmids, Mitsunori Fukuda for the SYT7-DN plasmid, Robert pbell for the GECO construct, Rob Onyenwoke for the human MCOLN1-EGFP, MCOLN1S51E-EGFP and MCOLN1S572E,S576E-EGFP, and Stephen Whitefield for his assistance in image analysis. We appreciate the encouragement and helpful comments from other members of the Dong laboratory. Funding Information: This work was supported by startup funds to X.D. from the Department of Physiology and Biophysics, Dalhousie University, DMRF Equipment Grant, DMRF new investigator award, CIHR grant (MOP-119349), CIHR New Investigator award (201109MSH-261462-208625), NSHRF Establishment Grant (MED-PRO-2011-7485), CFI Leaders Opportunity Fund-Funding for research infrastructure (29291), and the Program of International S and T Cooperation (2015DFA31580). We thank Lin Mei for the CALM plasmids, Michael X. Zhu for the LAMP1 plasmids, Mitsunori Fukuda for the SYT7-DN plasmid, Robert pbell for the GECO construct, Rob Onyenwoke for the human MCOLN1-EGFP, MCOLN1S51E-EGFP and MCOLN1S572E,S576E-EGFP, and Stephen Whitefield for his assistance in image analysis. We appreciate the encouragement and helpful comments from other members of the Dong laboratory. Publisher Copyright: © 2017 Taylor and Francis.

PY - 2018/1/2

Y1 - 2018/1/2

N2 - Macroautophagy/autophagy is an evolutionarily conserved pathway that is required for cellular homeostasis, growth and survival. The lysosome plays an essential role in autophagy regulation. For example, the activity of MTORC1, a master regulator of autophagy, is regulated by nutrients within the lysosome. Starvation inhibits MTORC1 causing autophagy induction. Given that MTORC1 is critical for protein synthesis and cellular homeostasis, a feedback regulatory mechanism must exist to restore MTORC1 during starvation. However, the molecular mechanism underlying this feedback regulation is unclear. In this study, we report that starvation activates the lysosomal Ca2+ release channel MCOLN1 (mucolipin 1) by relieving MTORC1's inhibition of the channel. Activated MCOLN1 in turn facilitates MTORC1 activity that requires CALM (calmodulin). Moreover, both MCOLN1 and CALM are necessary for MTORC1 reactivation during prolonged starvation. Our data suggest that lysosomal Ca2+ signaling is an essential component of the canonical MTORC1-dependent autophagy pathway and MCOLN1 provides a negative feedback regulation of MTORC1 to prevent excessive loss of MTORC1 function during starvation. The feedback regulation may be important for maintaining cellular homeostasis during starvation, as well as many other stressful or disease conditions.

AB - Macroautophagy/autophagy is an evolutionarily conserved pathway that is required for cellular homeostasis, growth and survival. The lysosome plays an essential role in autophagy regulation. For example, the activity of MTORC1, a master regulator of autophagy, is regulated by nutrients within the lysosome. Starvation inhibits MTORC1 causing autophagy induction. Given that MTORC1 is critical for protein synthesis and cellular homeostasis, a feedback regulatory mechanism must exist to restore MTORC1 during starvation. However, the molecular mechanism underlying this feedback regulation is unclear. In this study, we report that starvation activates the lysosomal Ca2+ release channel MCOLN1 (mucolipin 1) by relieving MTORC1's inhibition of the channel. Activated MCOLN1 in turn facilitates MTORC1 activity that requires CALM (calmodulin). Moreover, both MCOLN1 and CALM are necessary for MTORC1 reactivation during prolonged starvation. Our data suggest that lysosomal Ca2+ signaling is an essential component of the canonical MTORC1-dependent autophagy pathway and MCOLN1 provides a negative feedback regulation of MTORC1 to prevent excessive loss of MTORC1 function during starvation. The feedback regulation may be important for maintaining cellular homeostasis during starvation, as well as many other stressful or disease conditions.

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