TRP-ML1 Regulates Lysosomal pH and Acidic Lysosomal Lipid Hydrolytic Activity

Soyombo, Abigail A.; Tjon-Kon-Sang, Sandra; Rbaibi, Youssef; Bashllari, Enkelejda; Bisceglia, Jill; Muallem, Shmuel; Kiselyov, Kirill

doi:10.1074/jbc.m508211200

Cited by 209 publications

(241 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: Articlementioning

confidence: 53%

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: Articlementioning

confidence: 53%

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

et al. 2014

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“…We note that, unlike TPCs, evidence that TRPML1 functions as a Ca 2ϩ channel in the lysosomes or to participate in Ca 2ϩ release from other intracellular organelles is limited. However, TRPML1 has been shown to regulate lysosomal pH (23)(24)(25). Based on the available evidence, we thus suggest that TRPMLs and the TPCs may have different functions within the endo/lysosomal system.…”

Section: Resultsmentioning

confidence: 99%

“…The function of TRPMLs is known to a limited extent. TRPML1 is expressed largely in late endosomes and lysosomes (19 -22), where it appears to regulate lysosomal pH (23)(24)(25). Deletion of TRPML1 in mammalian cells (24,26,27) and Caenorhabditis elegans (21,28) indicate that TRPML1 is required for membrane trafficking.…”

Section: Camentioning

confidence: 99%

Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Yamaguchi

Jha

et al. 2011

Journal of Biological Chemistry

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104

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NAADP is a potent second messenger that mobilizes Ca 2؉from acidic organelles such as endosomes and lysosomes. The molecular basis for Ca 2؉ release by NAADP, however, is uncertain. TRP mucolipins (TRPMLs) and two-pore channels (TPCs) are Ca 2؉ -permeable ion channels present within the endolysosomal system. Both have been proposed as targets for NAADP. In the present study, we probed possible physical and functional association of these ion channels. Exogenously expressed TRPML1 showed near complete colocalization with TPC2 and partial colocalization with TPC1. TRPML3 overlap with TPC2 was more modest. TRPML1 and to some extent TRPML3 co-immunoprecipitated with TPC2 but less so with TPC1. Current recording, however, showed that TPC1 and TPC2 did not affect the activity of wild-type TRPML1 or constitutively active TRPML1(V432P). N-terminally truncated TPC2 (TPC2delN), which is targeted to the plasma membrane, also failed to affect TRPML1 and TRPML1 ( ؊/؊ cells. We conclude that although TRPML1 and TPCs are present in the same complex, they function as two independent organellar ion channels and that TPCs, not TRPMLs, are the targets for NAADP. Ca2ϩ plays a major role in the function of intracellular organelles including biosynthesis and membrane trafficking (1, 2). Although the mechanism controlling Ca 2ϩ in the endoplasmic reticulum has been studied extensively, very little is known about Ca 2ϩ homeostasis by other organelles. Furthermore, although accumulating evidence indicates that acidic organelles such as endosomes and lysosomes are dynamic Ca 2ϩ stores, the molecular basis for Ca 2ϩ release from these so-called "acidic Ca 2ϩ stores" (3) is at present defined poorly. By far, the best characterized route for mobilization of acidic Ca 2ϩ stores is through the production of the potent Ca 2ϩ -releasing second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP) 5 (4). The Ca 2ϩ -mobilizing properties of NAADP were discovered in sea urchin eggs (5), in which NAADP was shown to mobilize Ca 2ϩ not from the endoplasmic reticulum but instead from lysosome-related organelles (6). Its effects have subsequently been extended to a variety of cell types, including pancreatic acinar and ␤ cells, smooth muscle cells, neurons, and breast cancer cells (4). NAADP is produced by several extracellular stimuli in an agonist-specific manner and implicated in a number of physiological responses, including fertilization, glucose sensing, exocytosis, and neuronal growth (4). Deregulated lysosomal Ca 2ϩ signaling may also result in disease (2,7,8). Despite the physiological and potential pathophysiological importance of NAADP signaling, the molecular identity of the NAADP receptor is not entirely clear (9). Recently, members of the transient receptor potential mucolipin (TRPML) (10, 11) and two-pore channel (TPC) (12-16) families, which are all present in the endo/lysosomal system, have been proposed as candidates.TRPMLs form a subfamily of the superfamily of the TRP channels. The founding member is TRPML1, which was ide...

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“…Lactosylceramide has been used before to demonstrate abberrant trafficking in MLIV fibroblasts [40][41][42][43] . In the present study, we used BODIPY FL C5-LacCer and examined its distribution in WT and MLIV fibroblasts in pulse-chase experiments.…”

Section: Mk6-83 Effects On Trafficking and Lysosomal Zinc Buildupmentioning

confidence: 99%