title: Vps33b pathogenic mutations preferentially affect VIPAS39/SPE-39-positive endosomes.
abstract: Mutations in Vps33 isoforms cause pigment dilution in mice (Vps33a, buff) and Drosophila (car) and the neurogenic arthrogryposis, renal dysfunction and cholestasis syndrome in humans (ARC1, VPS33B). The later disease is also caused by mutations in VIPAS39, (Vps33b interacting protein, apical-basolateral polarity regulator, SPE-39 homolog; ARC2), a protein that interacts with the HOmotypic fusion and Protein Sorting (HOPS) complex, a tether necessary for endosome-lysosome traffic. These syndromes offer insight into fundamental endosome traffic processes unique to metazoans. However, the molecular and cellular mechanisms underlying these mutant phenotypes remain poorly understood. Here we investigate interactions of wild-type and disease-causing mutations in VIPAS39/SPE-39 and Vps33b by yeast two hybrid, immunoprecipitation and quantitative fluorescent microscopy. We find that although few mutations prevent interaction between VIPAS39/SPE-39 and Vps33b, some mutants fragment VIPAS39/SPE-39-positive endosomes, but all mutants alter the subcellular localization of Vps33b to VIPAS39/SPE-39-positive endosomes. Our data suggest that the ARC syndrome may result through impaired VIPAS39/SPE-39 and Vps33b-dependent endosomal maturation or fusion.
authors.affiliation: Department of Cell Biology.
authors.forename: Karine
authors.initials: K
authors.lastname: Tornieri
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Zlatic
authors.forename: Ariana P
authors.initials: AP
authors.lastname: Mullin
authors.forename: Erica
authors.initials: E
authors.lastname: Werner
authors.forename: Robert
authors.initials: R
authors.lastname: Harrison
authors.forename: Steven W
authors.initials: SW
authors.lastname: L'hernault
authors.forename: Victor
authors.initials: V
authors.lastname: Faundez
mesh_terms: D000818:Animals; D001176:Arthrogryposis / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002779:Cholestasis / Q000235:genetics* / Q000473:pathology; D011992:Endosomes / Q000235:genetics* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D051437:Renal Insufficiency / Q000235:genetics* / Q000473:pathology; D020798:Two-Hybrid System Techniques; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C531356:HOPS protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C539711:VIPAS39 protein, human; C411584:VPS33B protein, human; D033921:Vesicular Transport Proteins
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