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<p>Mammalian sterile-20-like kinase 1 (MST1) is a core component of the Hippo signaling pathway. A previous study of 24 patients with MST1 deficiency revealed that more than half of the patients presented symptoms of airway hyperresponsiveness and atopic dermatitis. We also found significantly reduced MST1 expression in patients with allergies and in mouse models of allergic asthma, suggesting that aberrant MST1 expression may be broadly relevant to allergic diseases. However, the specific mechanism by which MST1 may be related to allergic disorders has remained unclear. In our study, <i>Mst1</i><sup><i>-/-</i></sup> mice displayed exacerbated IgE-mediated allergic responses, including passive systemic and cutaneous anaphylaxis. More intriguingly, mast cell-deficient <i>Kit</i><sup><i>W-sh/W-sh</i></sup> mice reconstituted with <i>Mst1</i><sup><i>-/-</i></sup> bone marrow-derived mast cells (BMMCs) also presented aggravated IgE-mediated hypersensitivity reactions and mast cell-dependent asthma. MST1 deficiency notably promoted inflammatory cytokine production, cell degranulation, and intracellular calcium mobilization in FcεRI-stimulated BMMCs. Mechanistically, MST1 facilitates SRC homology domain-containing tyrosine phosphatase-1 (SHP-1)-mediated dephosphorylation of LCK/YES-related protein tyrosine kinase (LYN) at Y397 to repress FcɛRI signaling. Coimmunoprecipitation studies revealed that MST1 acts as a scaffold molecule to enhance the interaction between SHP-1 and LYN in a kinase activity-independent manner. Two patient-derived mutants presented significantly reduced intracellular protein expression levels and impaired LYN-SHP-1 interactions. Our study reveals a noncanonical role of MST1 in maintaining immune homeostasis by preventing mast cell-mediated hypersensitivity. This likely explains the increased susceptibility to allergic diseases in MST1-deficient patients.</p><p></p>

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MST1 bridges LYN and SHP-1 to suppress FcεRI-mediated mast cell activation and allergic responses

  • 期刊论文

  • 发表日期：

    2025年12月8日

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  • Mengyao Li,
  • Huihan Li,
  • Wenlong Lin,
  • Lin Tong,
  • Lingman Dai,
  • Qiannan Zhao,
  • Mengting Hu,
  • Zhimin Chen,
  • Yiting Zhou,
  • Qingqing Wang,
  • Yuanyuan Zhang

摘要

Mammalian sterile-20-like kinase 1 (MST1) is a core component of the Hippo signaling pathway. A previous study of 24 patients with MST1 deficiency revealed that more than half of the patients presented symptoms of airway hyperresponsiveness and atopic dermatitis. We also found significantly reduced MST1 expression in patients with allergies and in mouse models of allergic asthma, suggesting that aberrant MST1 expression may be broadly relevant to allergic diseases. However, the specific mechanism by which MST1 may be related to allergic disorders has remained unclear. In our study, Mst1-/- mice displayed exacerbated IgE-mediated allergic responses, including passive systemic and cutaneous anaphylaxis. More intriguingly, mast cell-deficient KitW-sh/W-sh mice reconstituted with Mst1-/- bone marrow-derived mast cells (BMMCs) also presented aggravated IgE-mediated hypersensitivity reactions and mast cell-dependent asthma. MST1 deficiency notably promoted inflammatory cytokine production, cell degranulation, and intracellular calcium mobilization in FcεRI-stimulated BMMCs. Mechanistically, MST1 facilitates SRC homology domain-containing tyrosine phosphatase-1 (SHP-1)-mediated dephosphorylation of LCK/YES-related protein tyrosine kinase (LYN) at Y397 to repress FcɛRI signaling. Coimmunoprecipitation studies revealed that MST1 acts as a scaffold molecule to enhance the interaction between SHP-1 and LYN in a kinase activity-independent manner. Two patient-derived mutants presented significantly reduced intracellular protein expression levels and impaired LYN-SHP-1 interactions. Our study reveals a noncanonical role of MST1 in maintaining immune homeostasis by preventing mast cell-mediated hypersensitivity. This likely explains the increased susceptibility to allergic diseases in MST1-deficient patients.