TRPML1: The Ca(2+)retaker of the lysosome

Paola, Simone Di; Rosato, Anna Scotto; Medina, Diego L.

doi:10.1016/j.ceca.2017.06.006

Cited by 119 publications

(124 citation statements)

References 136 publications

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“…As discussed above, lysosomal ion channels are master elements of lysosome activity and, thereby, of cell homeostasis. In the family of TRP channels, TRML1 is essential, being widely expressed in late endosomes and lysosomes, and preferentially associ ates with LAMP1 in the lysosomal membrane 22,301,302 . Genetic mutations leading to inactivation of TRPML1 cause a rare genetic disorder called mucolipidosis type IV (MLIV).…”

Section: V-atpase Inhibitorsmentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

500

374

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| Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases -including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease -this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

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Section: V-atpase Inhibitorsmentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

500

374

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“…All mammalian TRPML channels are stimulated on the cytoplasmic side by phosphatidylinositol 3,5‐bisphosphate (PI(3,5)P2), a phosphoinositide enriched in intracellular membranes, and, at least for TRPML1, antagonized by phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P2) enriched in the PM, suggesting elevated activity of TRPML channels when localized at lysosomal membranes. The TRPML1 channel is primarily localized in the late endolysosome compartment in mammalian cells and plays a role in many intracellular processes, including regulation of lysosomal biogenesis and autophagy . TRPML1 can reach the PM through the biosynthetic pathway from the Golgi apparatus or by lysosomal exocytosis .…”

Section: Molecular Regulation Of Autophagy Machinerymentioning

confidence: 99%

“…The TRPML1 channel is primarily localized in the late endolysosome compartment in mammalian cells and plays a role in many intracellular processes, including regulation of lysosomal biogenesis and autophagy . TRPML1 can reach the PM through the biosynthetic pathway from the Golgi apparatus or by lysosomal exocytosis . TRPML1‐deficient fibroblasts from mucolipidosis type IV patients exhibit enlargement and engulfment of the late endolysosomal compartment and accumulation of APs .…”

Section: Molecular Regulation Of Autophagy Machinerymentioning

confidence: 99%

“…TRPML1 can reach the PM through the biosynthetic pathway from the Golgi apparatus or by lysosomal exocytosis . TRPML1‐deficient fibroblasts from mucolipidosis type IV patients exhibit enlargement and engulfment of the late endolysosomal compartment and accumulation of APs . In addition, the defect in TRPML1‐mediated Ca 2+ release from late endosomes also impairs the fusion of amphisomes with lysosomes .…”

Section: Molecular Regulation Of Autophagy Machinerymentioning

confidence: 99%

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Molecular regulation of autophagy machinery by mTOR‐dependent and ‐independent pathways

Al‐Bari

2020

Annals of the New York Academy of Sciences

198

109

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Macroautophagy is a lysosomal degradative pathway or recycling process that maintains cellular homeostasis. This autophagy involves a series of sequential processing events, such as initiation; elongation and nucleation of the isolation membrane; cargo recruitment and maturation of the autophagosome (AP); transport of the AP; docking and fusion of the AP with a late endosome or lysosome; and regeneration of the lysosome by the autophagic lysosomal reformation cycle. These events are critically coordinated by the action of a set of several key components, including autophagy‐related proteins (Atg), and regulated by intricate networks, such as mechanistic target of rapamycin (mTOR), a master regulator of autophagy, as well as mTOR‐independent signaling pathways. Among mTOR‐independent pathways, the transient receptor potential (TRP) calcium ion channel TRPML (mucolipin) subfamily is emerging as an important signaling channel to modulate lysosomal biogenesis and autophagy. This review discusses the recent advances in elucidating the molecular mechanisms and regulation of the autophagy process. Understanding these mechanisms may ultimately allow scientists and clinicians to control this process in order to improve human health.

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“…We next aimed to delineate the mechanism by which an increase in intracellular Ca 2+ levels causes NOD-dependent pro-inflammatory signalling. We reasoned that since Ca 2+ regulates vesicular trafficking, exocytosis and recycling of lysosomes (24,25), it could thus in turn impact on the dynamic rate at which cells perform endocytosis. This led us to speculate that the Ca 2+ -dependent signal that triggers NOD-dependent activation in thapsigargin-stimulated cells could be coming from a factor within the extracellular milieu and be brought in by endocytosis.…”

Section: Dko Cells Rip2 Ko Hct116 Cells Displayed Normal Induction Omentioning

confidence: 99%

Trace levels of peptidoglycan in serum underlie the NOD-dependent cytokine response to endoplasmic reticulum stress

Molinaro

Flick

Philpott

et al. 2019

Preprint

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NOD1 and NOD2 are intracellular sensors of bacterial peptidoglycan that belong to the Nod-like receptor (NLR) family of innate immune proteins. In addition to their role as direct bacterial sensors, it was recently proposed that NOD proteins could detect endoplasmic reticulum (ER) stress induced by thapsigargin, an inhibitor of the sarcoplasmic or endoplasmic reticulum calcium ATPase family (SERCA) that pumps Ca 2+ into the ER, resulting in pro-inflammatory signalling. Here, we confirm that thapsigargin induces pro-inflammatory signalling in epithelial cells in a NODdependent manner. However, the effect was specific to thapsigargin, as tunicamycin and the subtilase cytotoxin SubAB from Shiga toxigenic Escherichia coli, which induce ER stress by other mechanisms, did not induce cytokine expression. The calcium ionophore A23187 also induced NOD-dependent signalling, and the calcium chelator BAPTA-AM blunted thapsigargin-dependent pro-inflammatory signalling, showing NOD proteins responded to a rise in intracellular Ca 2+ . Since intracellular Ca 2+ directly affects vesicular trafficking, we tested if thapsigargin-induced NOD activation required endocytosis. Our results demonstrate that both endocytosis and the addition of serum to the cell culture medium were required for thapsigarginmediated NOD activation. Finally, we analyzed cell culture grade fetal calf serum as well as serum from laboratory mice by high-pressure liquid chromatography and mass spectrometry, and identified the presence of various peptidoglycan fragments. We propose that cellular perturbations that affect intracellular Ca 2+ can trigger internalization of peptidoglycan trace contaminants found in culture serum, thereby stimulating pro-inflammatory signalling. The presence of peptidoglycan in animal serum suggests that a homeostatic function of NOD signalling may have been previously overlooked.

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TRPML1: The Ca(2+)retaker of the lysosome

Cited by 119 publications

References 136 publications

Lysosomes as a therapeutic target

Lysosomes as a therapeutic target

Molecular regulation of autophagy machinery by mTOR‐dependent and ‐independent pathways

Trace levels of peptidoglycan in serum underlie the NOD-dependent cytokine response to endoplasmic reticulum stress

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