HECT E3 ubiquitin ligase SMURF2 orchestrates FcεRI-dependent mast cell activation and allergic responses.

Cross-linking of IgE to its high-affinity receptor FcεRI on mast cells initiates intracellular signaling that drives the pathogenesis of allergic disorders, including asthma, allergic rhinitis, and atopic dermatitis. Precise regulation of mast cell signaling is essential for immune homeostasis and controlling allergic inflammation. We sought to explore the functional role of HECT E3 ubiquitin ligase SMURF2 in FcεRI-dependent mast cell activation and allergic responses, as well as the expression profile in allergic disease. We examined SMURF2 expression in mast cells from patients with allergic rhinitis, PBMCs and induced sputum from patients with acute asthma, and IgE-activated mast cells. The function of SMURF2 was assessed in vitro and in mast cell-specific Smurf2-deficient mice subjected to IgE-mediated anaphylaxis and ovalbumin-induced allergic airway disease. Molecular mechanisms were defined by co-immunoprecipitation and ubiquitination assays. SMURF2 was markedly upregulated in patient samples and stimulated mast cells. SMURF2 positively regulated IgE-dependent mast cell activation in vitro. Mast cell-specific Smurf2 deficiency attenuated passive systemic anaphylaxis and ovalbumin-induced allergic airway disease. Mechanistically, SMURF2 interacted with NEDD4L and promoted its K27-linked ubiquitination and proteasomal degradation, thereby enhancing Syk-mediated FcεRI signaling. SMURF2 is a critical positive regulator of mast cell activation and allergic responses by targeting NEDD4L for degradation to amplify Syk signaling. SMURF2 represents a potential diagnostic marker and therapeutic target for allergic diseases.