Rab44 regulates murine mast cell-driven anaphylaxis through kinesin-1-dependent secretory granule translocation.

ABSTRACT

BACKGROUND: Mast cells (MCs) are key effectors of the allergic response. Following the cross-linking of IgE receptors (FcεRIs), they release crucial inflammatory mediators through degranulation. Although degranulation depends critically on secretory granule (SG) trafficking toward the plasma membrane, the molecular machinery underlying this transport has not been fully characterized. OBJECTIVES: This study analyzed the function of Rab44, a large, atypical Rab guanosine triphosphatase highly expressed in MC, in the MC degranulation process. METHODS: Murine knockout (KO) mouse models (KORab44 and DKOKif5b/Rab44) were used to perform passive cutaneous anaphylaxis experiments and analyze granule translocation in bone marrow-derived MCs during degranulation. RESULTS: This study demonstrate that mice lacking Rab44 (KORab44) in their bone marrow-derived MCs are impaired in their ability to translocate and degranulate SGs at the plasma membrane on FcεRI stimulation. Accordingly, KORab44 mice were less sensitive to IgE-mediated passive cutaneous anaphylaxis in vivo. A lack of Rab44 did not impair early FcεRI-stimulated signaling pathways, microtubule reorganization, lipid mediator release, or cytokine secretion. Mechanistically, Rab44 appears to interact with and function as part of the previously described kinesin-1-dependent transport pathway. CONCLUSIONS: These results highlight a novel role of Rab44 as a regulator of SG transport during degranulation and anaphylaxis acting through the kinesin-1-dependent microtubule transport machinery. Rab44 can thus be considered a potential target for modulating MC degranulation and inhibiting IgE-mediated allergic reactions.