Ubiquitin-specific protease 13 regulates FcεRI-mediated mast cell activation and allergic inflammation via SYK protein modulation.

Mast cells (MCs) are therapeutic targets for high-affinity IgE Fc receptors (FcεRI)-mediated allergic responses. Deubiquitinating enzymes (DUBs), including ubiquitin-specific protease 13 (USP13), are involved in multiple inflammatory processes. This study aims to reveal USP13's role in FcεRI-mediated MC activation and its underlying mechanisms. Our results showed USP10/13 inhibitor spautin-1 inhibited IgE-mediated MC activation, as evidenced by a reduction in the release of β-hexosaminidase (β-hex) and histamine and decreased expression and secretion of inflammatory cytokines. Spautin-1 also attenuated inflammatory processes in IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models. Furthermore, knockdown of USP13 by short hairpin (sh)RNA diminished IgE-induced MC activation. Protein-protein interactions assays showed that USP13 interacted with the co-immunoprecipitated protein spleen tyrosine kinase (SYK) and deubiquitinated SYK. USP13 bound the kinase domain of SYK and removed its K63-linked polyubiquitination chain, yielding a more stable SYK protein. Importantly, 2-methoxyestradiol (2-Meth) was identified as a potential inhibitor of USP13 and inhibited FcεRI-mediated MC activation effectively in vitro and in vivo. In conclusion, it elucidated the molecular mechanism by which USP13 regulated SYK stability in MCs. The USP13-SYK axis may serve as a therapeutic target for treating FcεRI-mediated activation of MCs and associated inflammatory responses.