Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 205, Issue 6, Pages 1477-1490Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20072194
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Funding
- NCRR NIH HHS [TL1 RR024155, 5TL1RR024155-02] Funding Source: Medline
- NIDDK NIH HHS [DK54407, R01 DK054407] Funding Source: Medline
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The lysosomal storage disorder mucolipidosis type IV (MLIV) is caused by mutations in the transient receptor potential-mucolipin-1 (TRP-ML1) ion channel. The biogenesis model for MLIV pathogenesis suggests that TRP-ML1 modulates postendocytic delivery to lysosomes by regulating interactions between late endosomes and lysosomes. This model is based on observed lipid trafficking delays in MLIV patient fibroblasts. Because membrane traffic aberrations may be secondary to lipid buildup in chronically TRP-ML1-deficient cells, we depleted TRP-ML1 in HeLa cells using small interfering RNA and examined the effects on cell morphology and postendocytic traffic. TRP-ML1 knockdown induced gradual accumulation of membranous inclusions and, thus, represents a good model in which to examine the direct effects of acute TRP-ML1 deficiency on membrane traffic. Ratiometric imaging revealed decreased lysosomal pH in TRP-ML1-deficient cells, suggesting a disruption in lysosomal function. Nevertheless, we found no effect of TRP-ML1 knockdown on the kinetics of protein or lipid delivery to lysosomes. In contrast, by comparing degradation kinetics of low density lipoprotein constituents, we confirmed a selective defect in cholesterol but not apolipoprotein B hydrolysis in MLIV fibroblasts. We hypothesize that the effects of TRP-ML1 loss on hydrolytic activity have a cumulative effect on lysosome function, resulting in a lag between TRP-ML1 loss and full manifestation of MLIV.
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