USP5 deubiquitylates and stabilizes FcεRIγ to enhance IgE-induced mast cell activation and allergic inflammation.

Antigen-mediated aggregation of immunoglobulin E (IgE) bound to the high-affinity IgE receptor (FcεRI) initiates mast cell activation and allergic inflammation. Here, we investigated the role of ubiquitin-specific protease 5 (USP5) in IgE-mediated mast cell activation and its regulation of FcεRIγ stability. We found that USP5 knockdown inhibited the IgE-induced release of β-hexosaminidase and histamine from mast cells and attenuated allergic inflammation in mice. USP5 interacted with FcεRIγ in mast cells, leading to its deubiquitylation and stabilization. In addition, USP5 reversed the K48-linked polyubiquitylation of FcεRIγ. USP5 knockdown in mast cells or HEK293T cells increased the binding of the E3 ubiquitin ligase Cbl-b to FcεRIγ, leading to an increase in FcεRIγ polyubiquitylation and degradation. The USP5 inhibitor WP1130 attenuated IgE-mediated mast cell activation and allergic inflammation in mice. Together, these findings describe the molecular mechanism of USP5-mediated regulation of FcεRIγ stability in mast cells and identify the USP5-FcεRIγ axis as a potential drug target for the therapy of IgE/FcεRI-mediated allergic diseases.