Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disease characterized by severe psychomotor retardation, achlorhydria, and ophthalmological abnormalities. Cells from several tissues in MLIV patients accumulate large vacuoles that are presumed to be lysosomes, but whose exact nature remains to be determined. Other defects include the deterioration of neuronal integrity in the retina and the cerebellum. MCOLN1, the gene mutated in MLIV patients, encodes a protein called h-mucolipin-1 that has six predicted transmembrane domains and functions as a Ca 2؉ -permeable channel that is modulated by changes in Ca 2؉ concentration. CUP-5 is the Caenorhabditis elegans functional orthologue of h-mucolipin-1. Mutations in cup-5 result in the accumulation of large vacuoles in several cells, in increased cell death, and in embryonic lethality. We demonstrate here that CUP-5 functions in the biogenesis of lysosomes originating from hybrid organelles. We also show that at least two h-mucolipin family members rescue cup-5 mutant endocytic defects, indicating that there may be functional redundancy among the human proteins. Finally, we propose a model that relates the lysosome biogenesis defect in the absence of CUP-5͞h-mucolipin-1 to cellular phenotypes in worms and in humans.mucolipidosis type IV ͉ CUP-5
Ligand-gated ion channels are transmembrane proteins that respond to a variety of transmitters, including acetylcholine, gamma-aminobutyric acid (GABA), glycine, and glutamate [1 and 2]. These proteins play key roles in neurotransmission and are typically found in the nervous system and at neuromuscular junctions [3]. Recently, acetylcholine receptor family members also have been found in nonneuronal cells, including macrophages [4], keratinocytes [5], bronchial epithelial cells [5], and endothelial cells of arteries [6]. The function of these channels in nonneuronal cells in mammals remains to be elucidated, though it has been shown that the acetylcholine receptor alpha7 subunit is required for acetylcholine-mediated inhibition of tumor necrosis factor release by activated macrophages [4]. We show that cup-4, a gene required for efficient endocytosis of fluids by C. elegans coelomocytes, encodes a protein that is homologous to ligand-gated ion channels, with the highest degree of similarity to nicotinic acetylcholine receptors. Worms lacking CUP-4 have reduced phosphatidylinositol 4,5-bisphosphate levels at the plasma membrane, suggesting that CUP-4 regulates endocytosis through modulation of phospholipase C activity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.