title: Mast cell degranulation is negatively regulated by the Munc13-4-binding small-guanosine triphosphatase Rab37.
abstract: Mast cell degranulation is regulated by the small guanosine triphosphatases (GTPases) Rab27a and Rab27b, which have distinct and opposing roles: Rab27b acts as a positive regulator through its effector protein Munc13-4, a non-neuronal isoform of the vesicle-priming Munc13 family of proteins, whereas Rab27a acts as a negative regulator through its effector protein melanophilin, by maintaining integrity of cortical filamentous actin (F-actin), a barrier to degranulation. Here we investigated the role of Rab37, one of the Rab GTPases assumed to be implicated in regulated secretion during mast cell degranulation. Using the RBL-2H3 mast cell line, we detected Rab37 on the secretory granules and found that antigen-induced degranulation was extensively increased by either knockdown of Rab37 or overexpression of a dominant-active Rab37 mutant. This hypersecretion phenotype in the Rab37-knockdown cells was suppressed by simultaneous knockdown of Rab27a and Rab27b or of Munc13-4, but not by disruption of cortical F-actin. We further found that Rab37 interacted with Munc13-4 in a GTP-independent manner and formed a Rab27-Munc13-4-Rab37 complex. These results suggest that Rab37 is a Munc13-4-binding protein that inhibits mast cell degranulation through its effector protein, by counteracting the vesicle-priming activity of the Rab27-Munc13-4 system.
authors.affiliation: Department of Chemistry, Center for Liberal Arts and Sciences, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Higashio
authors.affiliation: Division of Cell Biology, Department of Anatomy, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.|Department of Medical Education, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Yoh-ichi
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Division of Cell Biology, Department of Anatomy, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Saino
mesh_terms: D000818:Animals; D015550:Cell Degranulation; D002460:Cell Line; D008407:Mast Cells / Q000166:cytology*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D011506:Proteins; C430713:Unc13d protein, rat; C000614432:Rab37 protein, rat; D020691:rab GTP-Binding Proteins