title: Defective relocalization of ALS2/alsin missense mutants to Rac1-induced macropinosomes accounts for loss of their cellular function and leads to disturbed amphisome formation.
abstract: Loss of ALS2/alsin function accounts for several recessive motor neuron diseases. ALS2 is a Rab5 activator and its endosomal localization is regulated by Rac1 via macropinocytosis. Here, we show that the pathogenic missense ALS2 mutants fail to be localized to Rac1-induced macropinosomes as well as endosomes, which leads to loss of the ALS2 function as a Rab5 activator on endosomes. Further, these mutants lose the competence to enhance the formation of amphisomes, the hybrid-organelle formed upon fusion between autophagosomes and endosomes. Thus, Rac1-induced relocalization of ALS2 might be crucial to exert the ALS2 function associated with the autophagy-endolysosomal degradative pathway.
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Otomo
authors.forename: Ryota
authors.initials: R
authors.lastname: Kunita
authors.forename: Kyoko
authors.initials: K
authors.lastname: Suzuki-Utsunomiya
authors.forename: Joh-E
authors.initials: JE
authors.lastname: Ikeda
authors.forename: Shinji
authors.initials: S
authors.lastname: Hadano
mesh_terms: D011992:Endosomes / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics*; D010588:Phagosomes / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D050505:Mutant Proteins; D018129:Phosphatidylinositol Phosphates; D020696:rab5 GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein