title: Rab31 and APPL2 enhance FcγR-mediated phagocytosis through PI3K/Akt signaling in macrophages.
abstract: Membrane remodeling in the early stages of phagocytosis enables the engulfment of particles or pathogens and receptor signaling to activate innate immune responses. Members of the Rab GTPase family and their disparate effectors are recruited sequentially to regulate steps throughout phagocytosis. Rab31 (Rab22b) is known for regulating post-Golgi trafficking, and here we show in macrophages that Rab31-GTP is additionally and specifically recruited to early-stage phagosomes. At phagocytic cups, Rab31 is first recruited during the phosphoinositide transition from PI(4,5)P2 to PI(3,4,5)P3, and it persists on PI(3)P-enriched phagosomes. During early phagocytosis, we find that Rab31 recruits the signaling adaptor APPL2. siRNA depletion of either Rab31 or APPL2 reduces FcγR-mediated phagocytosis. Mechanistically, this corresponds with a delay in the transition to PI(3,4,5)P3 and phagocytic cup closure. APPL2 depletion also reduced PI3K/Akt signaling and enhanced p38 signaling from FcγR. We thus conclude that Rab31/APPL2 is required for key roles in phagocytosis and prosurvival responses of macrophages. Of interest, in terms of localization and function, this Rab31/APPL2 complex is distinct from the Rab5/APPL1 complex, which is also involved in phagocytosis and signaling.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Yeo
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Wall
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane QLD 4072, Australia j.stow@imb.uq.edu.au.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D010587:Phagocytosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000602283:DCC-interacting protein 13-beta, mouse; C485701:Fcgr1 protein, mouse; D017452:Receptors, IgG; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C544741:Rab22B protein, mouse; D020691:rab GTP-Binding Proteins