Dynactin subunit 1 facilitates mast cell degranulation to drive food allergy pathogenesis

Background: Mast cells play pivotal roles in allergic pathogenesis and inflammatory disorders, with their pathologic effects largely mediated through granule exocytosis. Dynactin subunit 1 (Dctn1), a microtubule-associated motor protein, remains unexplored in mast cell-driven inflammation. This study investigates Dctn1's functional role in regulating mast cell degranulation during food allergy (FA). Methods: An ovalbumin-sensitized murine FA model was established to profile mast cell activity. Gut lavage fluid (GLF) was analyzed via Olink proteomics and ELISA to quantify Dctn1 levels and mast cell mediators (histamine, Mcpt1). Mechanistic studies employed RNA interference, conditional knockout mice (Dctn1(f/f) Cma1-Cre), and immunoprecipitation to assess Dctn1's role in granule trafficking. Results: FA mice exhibited 3.2-fold higher Dctn1 levels in GLF versus controls (p < 0.001), strongly correlating with mast cell mediator concentrations (histamine: r = 0.73; Mcpt1: r = 0.7). Intestinal mast cells showed selective Dctn1 upregulation (2.8-fold mRNA increase, p < 0.01), mechanistically linked to granule trafficking through CMA1 complex formation. Mast cell-specific Dctn1 ablation reduced Mcpt1 release by 74 % (p < 0.001) and ameliorated FA symptoms (92 % core temperature drop, p < 0.005), independent of AKT/ERK signaling pathways. Conclusions: This study identifies Dctn1 as a novel regulator of mast cell degranulation in FA, operating through microtubule-dependent granule transport. Targeted inhibition of Dctn1 significantly attenuates allergic responses without disrupting canonical activation signals, positioning it as a promising therapeutic target for mast cell-driven pathologies.