Abstract
To mediate the degradation of biomacromolecules, lysosomes must traffic towards cargo-carrying vesicles for subsequent membrane fusion or fission. Mutations of the lysosomal Ca(2+) channel TRPML1 cause lysosomal storage disease (LSD) characterized by disordered lysosomal membrane trafficking in cells. Here we show that TRPML1 activity is required to promote Ca(2+)-dependent centripetal movement of lysosomes towards the perinuclear region (where autophagosomes accumulate) following autophagy induction. ALG-2, an EF-hand-containing protein, serves as a lysosomal Ca(2+) sensor that associates physically with the minus-end-directed dynactin-dynein motor, while PtdIns(3,5)P(2), a lysosome-localized phosphoinositide, acts upstream of TRPML1. Furthermore, the PtdIns(3,5)P(2)-TRPML1-ALG-2-dynein signalling is necessary for lysosome tubulation and reformation. In contrast, the TRPML1 pathway is not required for the perinuclear accumulation of lysosomes observed in many LSDs, which is instead likely to be caused by secondary cholesterol accumulation that constitutively activates Rab7-RILP-dependent retrograde transport. Ca(2+) release from lysosomes thus provides an on-demand mechanism regulating lysosome motility, positioning and tubulation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Autophagy*
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Base Sequence
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COS Cells
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Calcium / metabolism*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cell Line
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Chlorocebus aethiops
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Dyneins / metabolism
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Fluorescence Recovery After Photobleaching
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HEK293 Cells
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HeLa Cells
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Humans
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Lysosomes / metabolism*
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Mice, Knockout
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Microscopy, Fluorescence
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Models, Biological
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Molecular Sequence Data
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Mutation
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Phosphatidylinositol Phosphates / metabolism
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Signal Transduction*
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Transient Receptor Potential Channels / genetics
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Transient Receptor Potential Channels / metabolism
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rab GTP-Binding Proteins / genetics
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rab GTP-Binding Proteins / metabolism
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rab7 GTP-Binding Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Calcium-Binding Proteins
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Luminescent Proteins
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Mcoln1 protein, mouse
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Pdcd6 protein, mouse
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Phosphatidylinositol Phosphates
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RILP protein, human
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Transient Receptor Potential Channels
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phosphatidylinositol 3,5-diphosphate
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rab7 GTP-Binding Proteins
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rab7 GTP-binding proteins, human
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rab7 GTP-binding proteins, mouse
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Dyneins
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rab GTP-Binding Proteins
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Calcium