No exit strategy for lipids

Lipids heading toward lysosomes that carry a mutated ion channel are spared from destruction, according to Meidel et al. (page 1477). The accumulating undigested fat eventually dooms the cell. Cells get rid of excess fat, which comes from worn-out organelles or engulfed pathogens by, for instance, shuttling them in endosomes to degradative lysosomes. The two organelles are thought to fuse when the lysosomal ion channel TRP-ML1 lets in calcium. Individuals with mutated TRP-ML1 suffer from a fatal disease called mucolipidosis type IV, which is characterized by fat accumulation in tissues. The failure of endosomes to fuse with lysosomes in these patients’ cells, as seen in previous imaging studies, was thought to cause the fat pile up and trigger disease. But because TRP-ML1 also lets through protons, which lowers the pH and thus activates lysosomal enzymes, Meidel et al. wondered whether the fat backlog is caused by a degradation defect rather than a fusion failure. By silencing TRP-ML1 in normal cells, the group now shows that the channel is not necessary for fusion. In its absence, however, lysosomes became overacidified and thus failed to process their lipid load. The pH defect suggests that the channel leaks protons out of the lysosome to prevent the interior from becoming too acidic. Lipid-clogged lysosomes might send feedback signals that prevent them from taking on new cargo. Retraining macrophages to kill tumors