title: Drosophila mauve mutants reveal a role of LYST homologs late in the maturation of phagosomes and autophagosomes.
abstract: Chediak-Higashi syndrome (CHS) is a lethal disease caused by mutations that inactivate the lysosomal trafficking regulator protein (LYST). Patients suffer from diverse symptoms including oculocutaneous albinism, recurrent infections, neutropenia and progressive neurodegeneration. These defects have been traced back to over-sized lysosomes and lysosome-related organelles (LROs) in different cell types. Here, we explore mutants in the Drosophila mauve gene as a new model system for CHS. The mauve gene (CG42863) encodes a large BEACH domain protein of 3535 amino acids similar to LYST. This reflects a functional homology between these proteins as mauve mutants also display enlarged LROs, such as pigment granules. This Drosophila model also replicates the enhanced susceptibility to infections and we show a defect in the cellular immune response. Early stages of phagocytosis proceed normally in mauve mutant hemocytes but, unlike in wild type, late phagosomes fuse and generate large vacuoles containing many bacteria. Autophagy is similarly affected in mauve fat bodies as starvation-induced autophagosomes grow beyond their normal size. Together these data suggest a model in which Mauve functions to restrict homotypic fusion of different pre-lysosomal organelles and LROs.
authors.affiliation: Department of Neuroscience, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9111, USA.
authors.forename: Mokhlasur
authors.initials: M
authors.lastname: Rahman
authors.forename: Adam
authors.initials: A
authors.lastname: Haberman
authors.forename: Charles
authors.initials: C
authors.lastname: Tracy
authors.forename: Sanchali
authors.initials: S
authors.lastname: Ray
authors.forename: Helmut
authors.initials: H
authors.lastname: Krämer
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D003594:Cytoplasmic Granules / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli; D006434:Hemocytes / Q000378:metabolism* / Q000382:microbiology / Q000648:ultrastructure; D007113:Immunity, Innate / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism; D009154:Mutation; D053141:Organelle Size / Q000235:genetics; D010587:Phagocytosis / Q000235:genetics; D010588:Phagosomes / Q000378:metabolism* / Q000648:ultrastructure; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D033921:Vesicular Transport Proteins; C581821:mv protein, Drosophila