Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release

Dongbiao Shen; Xiang Wang; Xinran Li; Xiaoli Zhang; Zepeng Yao; Shannon Dibble; Xian Ping Dong; Ting Yu; Andrew P. Lieberman; Hollis D. Showalter; Haoxing Xu

doi:10.1038/ncomms1735

Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release

Dongbiao Shen, Xiang Wang, Xinran Li, Xiaoli Zhang, Zepeng Yao, Shannon Dibble, Xian Ping Dong, Ting Yu, Andrew P. Lieberman, Hollis D. Showalter, Haoxing Xu

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399 Citations (Scopus)

Abstract

Lysosomal lipid accumulation, defects in membrane trafficking and altered Ca²⁺ homoeostasis are common features in many lysosomal storage diseases. Mucolipin transient receptor potential channel 1 (TRPML1) is the principle Ca²⁺ channel in the lysosome. Here we show that TRPML1-mediated lysosomal Ca²⁺ release, measured using a genetically encoded Ca²⁺ indicator (GCaMP3) attached directly to TRPML1 and elicited by a potent membrane-permeable synthetic agonist, is dramatically reduced in Niemann-Pick (NP) disease cells. Sphingomyelins (SMs) are plasma membrane lipids that undergo sphingomyelinase (SMase)-mediated hydrolysis in the lysosomes of normal cells, but accumulate distinctively in lysosomes of NP cells. Patch-clamp analyses revealed that TRPML1 channel activity is inhibited by SMs, but potentiated by SMases. In NP-type C cells, increasing TRPML1's expression or activity was sufficient to correct the trafficking defects and reduce lysosome storage and cholesterol accumulation. We propose that abnormal accumulation of luminal lipids causes secondary lysosome storage by blocking TRPML1- and Ca²⁺ -dependent lysosomal trafficking.

Original language	English
Article number	731
Journal	Nature Communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms1735
Publication status	Published - 2012
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by NIH RO1 grants (NS062792 to H.X and NS063967 to A.P.L.). WT control and NPC (NPC1−/−) CHO cells were a gift from Dr. T.Y. Chang at Dartmouth Medical School. We are grateful to Drs Susan Slaugenhaupt and Jim Pickel for TRPML1−/− mice, Dr. Loren Looger for the GCaMP3 construct, Dr. Yusuf Hannun for the DsRed-aSMase construct, and Richard Hume and Ken Cadigan for comments on an earlier version of the manuscript. We appreciate the encouragement and helpful comments from other members of the Xu laboratory.

ASJC Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms1735

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title = "Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release",

abstract = "Lysosomal lipid accumulation, defects in membrane trafficking and altered Ca2+ homoeostasis are common features in many lysosomal storage diseases. Mucolipin transient receptor potential channel 1 (TRPML1) is the principle Ca2+ channel in the lysosome. Here we show that TRPML1-mediated lysosomal Ca2+ release, measured using a genetically encoded Ca2+ indicator (GCaMP3) attached directly to TRPML1 and elicited by a potent membrane-permeable synthetic agonist, is dramatically reduced in Niemann-Pick (NP) disease cells. Sphingomyelins (SMs) are plasma membrane lipids that undergo sphingomyelinase (SMase)-mediated hydrolysis in the lysosomes of normal cells, but accumulate distinctively in lysosomes of NP cells. Patch-clamp analyses revealed that TRPML1 channel activity is inhibited by SMs, but potentiated by SMases. In NP-type C cells, increasing TRPML1's expression or activity was sufficient to correct the trafficking defects and reduce lysosome storage and cholesterol accumulation. We propose that abnormal accumulation of luminal lipids causes secondary lysosome storage by blocking TRPML1- and Ca2+ -dependent lysosomal trafficking.",

author = "Dongbiao Shen and Xiang Wang and Xinran Li and Xiaoli Zhang and Zepeng Yao and Shannon Dibble and Dong, {Xian Ping} and Ting Yu and Lieberman, {Andrew P.} and Showalter, {Hollis D.} and Haoxing Xu",

note = "Funding Information: This work was supported by NIH RO1 grants (NS062792 to H.X and NS063967 to A.P.L.). WT control and NPC (NPC1−/−) CHO cells were a gift from Dr. T.Y. Chang at Dartmouth Medical School. We are grateful to Drs Susan Slaugenhaupt and Jim Pickel for TRPML1−/− mice, Dr. Loren Looger for the GCaMP3 construct, Dr. Yusuf Hannun for the DsRed-aSMase construct, and Richard Hume and Ken Cadigan for comments on an earlier version of the manuscript. We appreciate the encouragement and helpful comments from other members of the Xu laboratory.",

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doi = "10.1038/ncomms1735",

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AU - Shen, Dongbiao

AU - Wang, Xiang

AU - Li, Xinran

AU - Zhang, Xiaoli

AU - Yao, Zepeng

AU - Dibble, Shannon

AU - Dong, Xian Ping

AU - Yu, Ting

AU - Lieberman, Andrew P.

AU - Showalter, Hollis D.

AU - Xu, Haoxing

N1 - Funding Information: This work was supported by NIH RO1 grants (NS062792 to H.X and NS063967 to A.P.L.). WT control and NPC (NPC1−/−) CHO cells were a gift from Dr. T.Y. Chang at Dartmouth Medical School. We are grateful to Drs Susan Slaugenhaupt and Jim Pickel for TRPML1−/− mice, Dr. Loren Looger for the GCaMP3 construct, Dr. Yusuf Hannun for the DsRed-aSMase construct, and Richard Hume and Ken Cadigan for comments on an earlier version of the manuscript. We appreciate the encouragement and helpful comments from other members of the Xu laboratory.

PY - 2012

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N2 - Lysosomal lipid accumulation, defects in membrane trafficking and altered Ca2+ homoeostasis are common features in many lysosomal storage diseases. Mucolipin transient receptor potential channel 1 (TRPML1) is the principle Ca2+ channel in the lysosome. Here we show that TRPML1-mediated lysosomal Ca2+ release, measured using a genetically encoded Ca2+ indicator (GCaMP3) attached directly to TRPML1 and elicited by a potent membrane-permeable synthetic agonist, is dramatically reduced in Niemann-Pick (NP) disease cells. Sphingomyelins (SMs) are plasma membrane lipids that undergo sphingomyelinase (SMase)-mediated hydrolysis in the lysosomes of normal cells, but accumulate distinctively in lysosomes of NP cells. Patch-clamp analyses revealed that TRPML1 channel activity is inhibited by SMs, but potentiated by SMases. In NP-type C cells, increasing TRPML1's expression or activity was sufficient to correct the trafficking defects and reduce lysosome storage and cholesterol accumulation. We propose that abnormal accumulation of luminal lipids causes secondary lysosome storage by blocking TRPML1- and Ca2+ -dependent lysosomal trafficking.

AB - Lysosomal lipid accumulation, defects in membrane trafficking and altered Ca2+ homoeostasis are common features in many lysosomal storage diseases. Mucolipin transient receptor potential channel 1 (TRPML1) is the principle Ca2+ channel in the lysosome. Here we show that TRPML1-mediated lysosomal Ca2+ release, measured using a genetically encoded Ca2+ indicator (GCaMP3) attached directly to TRPML1 and elicited by a potent membrane-permeable synthetic agonist, is dramatically reduced in Niemann-Pick (NP) disease cells. Sphingomyelins (SMs) are plasma membrane lipids that undergo sphingomyelinase (SMase)-mediated hydrolysis in the lysosomes of normal cells, but accumulate distinctively in lysosomes of NP cells. Patch-clamp analyses revealed that TRPML1 channel activity is inhibited by SMs, but potentiated by SMases. In NP-type C cells, increasing TRPML1's expression or activity was sufficient to correct the trafficking defects and reduce lysosome storage and cholesterol accumulation. We propose that abnormal accumulation of luminal lipids causes secondary lysosome storage by blocking TRPML1- and Ca2+ -dependent lysosomal trafficking.

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Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release

Abstract

Bibliographical note

ASJC Scopus Subject Areas

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