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
A series of squarylium cyanine dyes with different substituents were synthesized and the third-order optical nonlinearities of their ground and excited states were investigated by backward degenerate four-wave-mixing....A series of squarylium cyanine dyes with different substituents were synthesized and the third-order optical nonlinearities of their ground and excited states were investigated by backward degenerate four-wave-mixing.For the ground state,the molecular hyperpolarizabilityγg increases with the red-shift of the absorption peakλabmax,of the squaraine with different substituents,whereas for the excited-state molecular hyperpolarizabilityγe,the nonlinear enhancementγe/γg decreases,which may indicate that in the excited state the electron accepting-donating ability of different substituents changes in the reverse order compared with the order in the ground state.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.
基金the National Natural Science Foundation of China under Grant Nos.19734040,and 69778014.
文摘A series of squarylium cyanine dyes with different substituents were synthesized and the third-order optical nonlinearities of their ground and excited states were investigated by backward degenerate four-wave-mixing.For the ground state,the molecular hyperpolarizabilityγg increases with the red-shift of the absorption peakλabmax,of the squaraine with different substituents,whereas for the excited-state molecular hyperpolarizabilityγe,the nonlinear enhancementγe/γg decreases,which may indicate that in the excited state the electron accepting-donating ability of different substituents changes in the reverse order compared with the order in the ground state.
