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

  • Int J Biol Macromol. 2025 May;308(Pt 2):142302. doi: 10.1016/j.ijbiomac.2025.142302.
Yan-Mei Zhou  1 ,  Yu-Xin Jiao  2 ,  Jun-Kai Fan  3 ,  Run-Xin Zhang  4 ,  Shan Liu  2 ,  Xue-Ting Xu  2 ,  Rongfei Zhu  5 ,  Kunmei Ji  6 ,  Jia-Jie Chen  7
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China; School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.
  • 2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.
  • 3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China. Electronic address: [email protected].
  • 4. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China. Electronic address: [email protected].
  • 5. Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: [email protected].
  • 6. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China; School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China. Electronic address: [email protected].
  • 7. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China. Electronic address: [email protected].
PMID: 40139593 DOI: 10.1016/j.ijbiomac.2025.142302
Abstract

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.

Keywords
2-Methoxyestradiol (PubChem CID: 66414); Mast cell; SYK; Spautin-1 (PubChem CID: 51037431); USP13.
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