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

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

doi:10.1038/ncomms1735

Cited by 427 publications

(649 citation statements)

References 39 publications

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“…5f). Filipin [39][40][41][42] stainings further confirmed a strong accumulation of cholesterol in TPC2 À / À hepatocytes after CD treatment (Fig. 6a).…”

Section: Articlesupporting

confidence: 54%

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.

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“…5f). Filipin [39][40][41][42] stainings further confirmed a strong accumulation of cholesterol in TPC2 À / À hepatocytes after CD treatment (Fig. 6a).…”

Section: Articlesupporting

confidence: 54%

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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“…In human, loss-of-function mutations in TRPML1 are the direct cause of Mucolipidosis type IV (MLIV), an autosomal recessive lysosomal storage disease characterized by abnormal neurodevelopment, retinal degeneration and iron-deficiency anemia 3-6 . Due to its direct linkage to MLIV disease, TRPML1 has been a potential target for small molecule therapeutics and several synthetic small molecule agonists have been developed 12,20 .…”

Section: Main Textmentioning

confidence: 99%

Structure of mammalian endolysosomal TRPML1 channel in nanodiscs

Chen

She

Zeng

et al. 2017

Nature

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268

170

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Transient receptor potential mucolipin 1 (TRPML1) is an endo/lysosomal cation channel ubiquitously expressed in mammalian cells1,2 and its loss-of-function mutations are the direct cause of Type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease3-6. Here we present the single particle cryo-electron microscopy (cryo-EM) structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis, the TRPML1 structure reveals that phosphatidylinositol bisphosphate (PIP2) binds to the N-terminus of the channel – distal from the pore – and the helix-turn-helix extension between S2 and S3 likely couples ligand binding to pore opening. The tightly packed selectivity filter contains multiple ion binding sites and the conserved acidic residues form the luminal Ca2+ blocking site that confers luminal pH and Ca2+ modulation on channel conductance. A luminal linker domain forms a fenestrated canopy atop the channel, providing multiple luminal ion passages to the pore and also creating a negative electrostatic trap – preferably for divalent cations at the luminal entrance. The structure also reveals two equally distributed S4-S5 linker conformations in the closed channel, providing structural implication for the S4-S5 linker-mediated PIP2 gating mechanism among TRPML channels7,8.

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“…response to trafficking cues, such as changes in levels of PI(3,5)P 2 , a lysosome-localized phosphoinositide (7,15,(18)(19)(20)(21). ML1-mediated lysosomal Ca 2+ release may regulate many aspects of lysosomal trafficking, including lysosome to trans-Golgi-network (TGN) retrograde trafficking, autophagosome-lysosome fusion, lysosome reformation, and lysosomal exocytosis (15,19,22,23).…”

Section: Significancementioning

confidence: 99%

“…ML1-mediated lysosomal Ca 2+ release may regulate many aspects of lysosomal trafficking, including lysosome to trans-Golgi-network (TGN) retrograde trafficking, autophagosome-lysosome fusion, lysosome reformation, and lysosomal exocytosis (15,19,22,23). Moreover, it has been demonstrated that nutrient starvation affects phosphoinositide dynamics and Ca 2+ signaling (16,18,24).…”

Section: Significancementioning

confidence: 99%

Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation

Wang

Gao

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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203

182

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Upon nutrient starvation, autophagy digests unwanted cellular components to generate catabolites that are required for housekeeping biosynthesis processes. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Here, we report that mucolipin-1 (also known as TRPML1 or ML1), a Ca 2+ channel in the lysosome that regulates many aspects of lysosomal trafficking, plays a central role in this quality-control process. By using Ca 2+ imaging and whole-lysosome patch clamping, lysosomal Ca 2+ release and ML1 currents were detected within hours of nutrient starvation and were potently up-regulated. In contrast, lysosomal Na + -selective currents were not upregulated. Inhibition of mammalian target of rapamycin (mTOR) or activation of transcription factor EB (TFEB) mimicked a starvation effect in fed cells. The starvation effect also included an increase in lysosomal proteostasis and enhanced clearance of lysosomal storage, including cholesterol accumulation in Niemann-Pick disease type C (NPC) cells. However, this effect was not observed when ML1 was pharmacologically inhibited or genetically deleted. Furthermore, overexpression of ML1 mimicked the starvation effect. Hence, lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca 2+ signaling.

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

Cited by 427 publications

References 39 publications

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

Structure of mammalian endolysosomal TRPML1 channel in nanodiscs

Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation

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