title: Rab12 Regulates Retrograde Transport of Mast Cell Secretory Granules by Interacting with the RILP-Dynein Complex.
abstract: Secretory granule (SG) transport is a critical step in regulated exocytosis including degranulation of activated mast cells. The latter process results in the release of multiple inflammatory mediators that play key roles in innate immunity, as well as in allergic responses. In this study, we identified the small GTPase Rab12 as a novel regulator of mast cell SG transport, and we provide mechanistic insights into its mode of action. We show that Rab12 is activated in a stimulus-dependent fashion and promotes microtubule-dependent retrograde transport of the SGs in the activated cells. We also show that this minus end transport of the SGs is mediated by the RILP-dynein complex and identify RILP as a novel effector of Rab12. Finally, we show that Rab12 negatively regulates mast cell degranulation. Taken together, our results identify Rab12 as a novel regulator of mast cell responses and disclose for the first time, to our knowledge, the mechanism of retrograde transport of the mast cell SGs.
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Adi
authors.initials: A
authors.lastname: Efergan
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Nurit P
authors.identifier: http://orcid.org/0000-0002-0221-8439
authors.initials: NP
authors.lastname: Azouz
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
authors.forename: Ofir
authors.initials: O
authors.lastname: Klein
authors.affiliation: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan; and.
authors.forename: Kenta
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan; and.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; histol3@post.tau.ac.il.
authors.forename: Ronit
authors.identifier: http://orcid.org/0000-0002-1990-8831
authors.initials: R
authors.lastname: Sagi-Eisenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D015550:Cell Degranulation / Q000276:immunology*; D002460:Cell Line; D004398:Dyneins / Q000276:immunology / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D021381:Protein Transport / Q000276:immunology; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D022142:Secretory Vesicles / Q000276:immunology / Q000378:metabolism*; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C557700:RILP protein, rat; C503898:rab12 protein, rat; D004398:Dyneins; D020691:rab GTP-Binding Proteins