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
Porcine reproductive and respiratory syndrome virus(PRRSV) shows characteristic antibody-dependent enhancement(ADE) of infection and causes porcine systemic inflammation, which is similar to a type I allergic reaction...Porcine reproductive and respiratory syndrome virus(PRRSV) shows characteristic antibody-dependent enhancement(ADE) of infection and causes porcine systemic inflammation, which is similar to a type I allergic reaction; however, the role of porcine FceεRI in ADE is still unclear. In this study, the expression of different Fc receptors(Fc Rs) on macrophages was investigated in a PRRSV 3D4/21 cell infection model in the presence or absence of PRRSV antibody. The transcription level of Fcc II and FceεRI was significantly up-regulated under PRRSV-antibody complex infection. Internalization and proliferation of PRRSV were promoted by the ADE mechanism when FceεRI was expressed in permissive 3D4/21 cells and the non-permissive cell line HEK 293T. Transcriptome sequencing data showed that the expression levels of AKT,ERK and other signal molecules in the anti-inflammatory pathway were significantly increased, especially in the cells infected with the PRRSV-antibody immune complex. Inflammatory regulatory molecules such as PLA2G6, LOX, TRPM8 and TRPM4 were significantly up-regulated following PRRSV infection but significantly down-regulated in the cells infected with the PRRSV-antibody immune complex. Our results demonstrated that FceεRI could be involved in PRRSV ADE, the antigen presenting process and regulation of the inflammatory response during PRRSV infection, which provides new insights into PRRSV infection mediated by FceεRI and the PRRSV-antibody immune complex.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supported by the National Natural Science Foundation of China (31272540)the underprop project of Tianjin Science and Technology Committee in China (16YFZCNC00640)
文摘Porcine reproductive and respiratory syndrome virus(PRRSV) shows characteristic antibody-dependent enhancement(ADE) of infection and causes porcine systemic inflammation, which is similar to a type I allergic reaction; however, the role of porcine FceεRI in ADE is still unclear. In this study, the expression of different Fc receptors(Fc Rs) on macrophages was investigated in a PRRSV 3D4/21 cell infection model in the presence or absence of PRRSV antibody. The transcription level of Fcc II and FceεRI was significantly up-regulated under PRRSV-antibody complex infection. Internalization and proliferation of PRRSV were promoted by the ADE mechanism when FceεRI was expressed in permissive 3D4/21 cells and the non-permissive cell line HEK 293T. Transcriptome sequencing data showed that the expression levels of AKT,ERK and other signal molecules in the anti-inflammatory pathway were significantly increased, especially in the cells infected with the PRRSV-antibody immune complex. Inflammatory regulatory molecules such as PLA2G6, LOX, TRPM8 and TRPM4 were significantly up-regulated following PRRSV infection but significantly down-regulated in the cells infected with the PRRSV-antibody immune complex. Our results demonstrated that FceεRI could be involved in PRRSV ADE, the antigen presenting process and regulation of the inflammatory response during PRRSV infection, which provides new insights into PRRSV infection mediated by FceεRI and the PRRSV-antibody immune complex.
