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...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 Kit^(W-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.展开更多
新生儿Fc受体(neonatal Fc receptor,FcRn)通过与免疫球蛋G(immunoglobulin G,IgG)结合,延长其半衰期并促进再循环,是维持血清IgG稳态的重要受体。然而,致病性IgG的异常积累与多种神经免疫性疾病的发生密切相关。FcRn拮抗剂通过阻断FcRn...新生儿Fc受体(neonatal Fc receptor,FcRn)通过与免疫球蛋G(immunoglobulin G,IgG)结合,延长其半衰期并促进再循环,是维持血清IgG稳态的重要受体。然而,致病性IgG的异常积累与多种神经免疫性疾病的发生密切相关。FcRn拮抗剂通过阻断FcRn与IgG的结合,可显著降低致病性IgG水平,从而有效地缓解相关疾病的临床症状。FcRn拮抗剂作为一种新兴的靶向治疗药物,展示了其治疗IgG介导的神经免疫性疾病的潜力。本文对FcRn拮抗剂的作用机制、种类和临床研究进展进行总结,以期为IgG介导的神经免疫性疾病的精准治疗提供新思路。未来的研究应重点关注药物的长期安全性、适应证拓展及个体化治疗策略,以进一步提升其临床应用价值。展开更多
基金supported by grants from the National Natural Science Foundation of China(8187060308,U22A20307,and 81930041)the Key R&D Program of Zhejiang Province(2024C03177)+1 种基金the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2024ZD0541200)the Natural Science Foundation of Zhejiang Province(LZ24H100001).
文摘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 Kit^(W-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.
文摘新生儿Fc受体(neonatal Fc receptor,FcRn)通过与免疫球蛋G(immunoglobulin G,IgG)结合,延长其半衰期并促进再循环,是维持血清IgG稳态的重要受体。然而,致病性IgG的异常积累与多种神经免疫性疾病的发生密切相关。FcRn拮抗剂通过阻断FcRn与IgG的结合,可显著降低致病性IgG水平,从而有效地缓解相关疾病的临床症状。FcRn拮抗剂作为一种新兴的靶向治疗药物,展示了其治疗IgG介导的神经免疫性疾病的潜力。本文对FcRn拮抗剂的作用机制、种类和临床研究进展进行总结,以期为IgG介导的神经免疫性疾病的精准治疗提供新思路。未来的研究应重点关注药物的长期安全性、适应证拓展及个体化治疗策略,以进一步提升其临床应用价值。
