title: ESCRT-Dependent Cell Death in a Caenorhabditis elegans Model of the Lysosomal Storage Disorder Mucolipidosis Type IV.
abstract: Mutations in MCOLN1, which encodes the cation channel protein TRPML1, result in the neurodegenerative lysosomal storage disorder Mucolipidosis type IV. Mucolipidosis type IV patients show lysosomal dysfunction in many tissues and neuronal cell death. The ortholog of TRPML1 in Caenorhabditis elegans is CUP-5; loss of CUP-5 results in lysosomal dysfunction in many tissues and death of developing intestinal cells that results in embryonic lethality. We previously showed that a null mutation in the ATP-Binding Cassette transporter MRP-4 rescues the lysosomal defect and embryonic lethality of cup-5(null) worms. Here we show that reducing levels of the Endosomal Sorting Complex Required for Transport (ESCRT)-associated proteins DID-2, USP-50, and ALX-1/EGO-2, which mediate the final de-ubiquitination step of integral membrane proteins being sequestered into late endosomes, also almost fully suppresses cup-5(null) mutant lysosomal defects and embryonic lethality. Indeed, we show that MRP-4 protein is hypo-ubiquitinated in the absence of CUP-5 and that reducing levels of ESCRT-associated proteins suppresses this hypo-ubiquitination. Thus, increased ESCRT-associated de-ubiquitinating activity mediates the lysosomal defects and corresponding cell death phenotypes in the absence of CUP-5.
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Huynh
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Hope
authors.initials: H
authors.lastname: Dang
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Isabel A
authors.initials: IA
authors.lastname: Munoz-Tucker
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Marvin
authors.initials: M
authors.lastname: O'Ketch
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Liu
authors.affiliation: Sahuaro High School, Tucson, Arizona 85710.
authors.forename: Savannah
authors.initials: S
authors.lastname: Perno
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Natasha
authors.initials: N
authors.lastname: Bhuyan
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Allison
authors.initials: A
authors.lastname: Crain
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Ivan
authors.initials: I
authors.lastname: Borbon
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721 fares@email.arizona.edu.
authors.forename: Hanna
authors.initials: H
authors.lastname: Fares
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D016923:Cell Death; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D055786:Gene Knockout Techniques; D005804:Genes, Lethal; D008247:Lysosomes / Q000378:metabolism; D009081:Mucolipidoses / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D034622:RNA Interference; D054875:Ubiquitination
chemical_list: D029742:Caenorhabditis elegans Proteins; D056827:Endosomal Sorting Complexes Required for Transport
keywords: CUP-5; ESCRT; TRPML1; lysosome; mucolipidosis type IV