title: Arl8/ARL-8 functions in apoptotic cell removal by mediating phagolysosome formation in Caenorhabditis elegans.
abstract: Efficient clearance of apoptotic cells by phagocytes is important for development, tissue homeostasis, and the prevention of autoimmune responses. Phagosomes containing apoptotic cells undergo acidification and mature from Rab5-positive early to Rab7-positive late stages. Phagosomes finally fuse with lysosomes to form phagolysosomes, which degrade apoptotic cells; however, the molecular mechanism underlying phagosome-lysosome fusion is not fully understood. Here we show that the Caenorhabditis elegans Arf-like small GTPase Arl8 (ARL-8) is involved in phagolysosome formation and is required for the efficient removal of apoptotic cells. Loss of function of arl-8 results in the accumulation of apoptotic germ cells. Both the engulfment of the apoptotic cells by surrounding somatic sheath cells and the phagosomal maturation from RAB-5- to RAB-7-positive stages occur in arl-8 mutants. However, the phagosomes fail to fuse with lysosomes in the arl-8 mutants, leading to the accumulation of RAB-7-positive phagosomes and the delayed degradation of apoptotic cells. ARL-8 localizes primarily to lysosomes and physically interacts with the homotypic fusion and protein sorting complex component VPS-41. Collectively our findings reveal that ARL-8 facilitates apoptotic cell removal in vivo by mediating phagosome-lysosome fusion during phagocytosis.
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Sasaki
authors.forename: Isei
authors.initials: I
authors.lastname: Nakae
authors.forename: Maya
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Fumiko
authors.initials: F
authors.lastname: Abe
authors.forename: Kota
authors.initials: K
authors.lastname: Saito
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Fukuyama
authors.forename: Keiko
authors.initials: K
authors.lastname: Gengyo-Ando
authors.forename: Shohei
authors.initials: S
authors.lastname: Mitani
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Katada
authors.forename: Kenji
authors.initials: K
authors.lastname: Kontani
mesh_terms: D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000166:cytology / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D020558:GTP Phosphohydrolases / Q000502:physiology*; D005854:Germ Cells / Q000502:physiology; D006066:Gonads / Q000166:cytology / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology; D010588:Phagosomes / Q000201:enzymology*; D021381:Protein Transport; D059008:Time-Lapse Imaging; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D029742:Caenorhabditis elegans Proteins; D033921:Vesicular Transport Proteins; D000090802:rab7 GTP-Binding Proteins; D020558:GTP Phosphohydrolases; C552949:arl-8 protein, C elegans; D020691:rab GTP-Binding Proteins