Osteoarthritis(OA),the most prevalent degenerative joint disease,is marked by cartilage degradation and pathological alterations in surrounding tissues.Currently,no effective disease-modifying treatments exist.This st...Osteoarthritis(OA),the most prevalent degenerative joint disease,is marked by cartilage degradation and pathological alterations in surrounding tissues.Currently,no effective disease-modifying treatments exist.This study aimed to elucidate the critical roles of Myb-like,SWIRM,and MPN domains 1(MYSM1)and its downstream effector,Receptor-interacting protein kinase 2(RIPK2),in OA pathogenesis and the underlying mechanisms.Our findings revealed reduced MYSM1 levels in the cartilage of OA patients and mouse models.Genetic or adenovirus-induced MYSM1 knockout exacerbated OA progression in mice,whereas MYSM1 overexpression mitigated it.Mechanistically,MYSM1 inhibited the NF-κB and MAPK signaling pathways.Conversely,downstream RIPK2 significantly increased OA-like phenotypes and activated the NF-κB and MAPK pathways.The Ripk2^(S176D) mutation accelerated OA pathogenesis,while Ripk2 silencing or Ripk2^(S176A)mutation deactivated NF-κB and MAPK pathways,counteracting the role of MYSM1.MYSM1 deubiquitinates and dephosphorylates RIPK2^(S176)by recruiting protein phosphatase 2 A(PP2A).These results suggest that targeting MYSM1 or downstream RIPK2 offers promising therapeutic potential for OA.展开更多
PP2Cs(2C type protein phosphatases)是一种单体丝氨酸/苏氨酸蛋白磷酸酶,在真核生物中,PP2Cs在脱落酸(ABA)、茉莉酸(JA)、水杨酸(SA)等激素信号传导途径中起着重要的调控作用。本研究通过序列比对,从谷子基因组中筛选出80个PP2C候选基...PP2Cs(2C type protein phosphatases)是一种单体丝氨酸/苏氨酸蛋白磷酸酶,在真核生物中,PP2Cs在脱落酸(ABA)、茉莉酸(JA)、水杨酸(SA)等激素信号传导途径中起着重要的调控作用。本研究通过序列比对,从谷子基因组中筛选出80个PP2C候选基因,聚类分析将其分为12个亚族(A、B、C、D、E1、E2、F1、F2、G、H、I、J)。与拟南芥PP2C基因家族比对表明,A^I为2个物种共有的亚族,J亚族只存在于谷子基因组中,L亚族只存在于拟南芥中。将谷子A亚族的10个成员命名为SiPP2CA1-10。基因表达谱分析表明,A亚族基因不同程度受ABA、干旱、高盐、低温和低氮诱导表达,其中,SiPP2CA6、SiPP2CA8在5种处理下诱导表达量都高。对10个A亚族成员的启动子分析发现,在这些基因的启动子序列中含有多种参与逆境胁迫应答的顺式作用元件,其中,SiPP2CA5、SiPP2CA6、SiPP2CA7、SiPP2CA8的启动子中含有参与低氮胁迫响应的元件。进一步研究发现,SiPP2CA8主要在根部表达,且在低氮胁迫下一直有较高的表达水平。亚细胞定位结果显示SiPP2CA8定位在细胞膜、细胞质、细胞核中;双分子荧光互补试验(BiFC)结果表明,SiPP2CA8与一个ABA受体类似蛋白SiRCAR3(基因号为Si018317m.g)在细胞膜、细胞质及细胞核上互作,表明SiPP2CA8在谷子中可能参与ABA信号传导过程。展开更多
基金National Natural Science Foundation of China(Nos.82330075 and 81401047)Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZC20241275)。
文摘Osteoarthritis(OA),the most prevalent degenerative joint disease,is marked by cartilage degradation and pathological alterations in surrounding tissues.Currently,no effective disease-modifying treatments exist.This study aimed to elucidate the critical roles of Myb-like,SWIRM,and MPN domains 1(MYSM1)and its downstream effector,Receptor-interacting protein kinase 2(RIPK2),in OA pathogenesis and the underlying mechanisms.Our findings revealed reduced MYSM1 levels in the cartilage of OA patients and mouse models.Genetic or adenovirus-induced MYSM1 knockout exacerbated OA progression in mice,whereas MYSM1 overexpression mitigated it.Mechanistically,MYSM1 inhibited the NF-κB and MAPK signaling pathways.Conversely,downstream RIPK2 significantly increased OA-like phenotypes and activated the NF-κB and MAPK pathways.The Ripk2^(S176D) mutation accelerated OA pathogenesis,while Ripk2 silencing or Ripk2^(S176A)mutation deactivated NF-κB and MAPK pathways,counteracting the role of MYSM1.MYSM1 deubiquitinates and dephosphorylates RIPK2^(S176)by recruiting protein phosphatase 2 A(PP2A).These results suggest that targeting MYSM1 or downstream RIPK2 offers promising therapeutic potential for OA.
文摘PP2Cs(2C type protein phosphatases)是一种单体丝氨酸/苏氨酸蛋白磷酸酶,在真核生物中,PP2Cs在脱落酸(ABA)、茉莉酸(JA)、水杨酸(SA)等激素信号传导途径中起着重要的调控作用。本研究通过序列比对,从谷子基因组中筛选出80个PP2C候选基因,聚类分析将其分为12个亚族(A、B、C、D、E1、E2、F1、F2、G、H、I、J)。与拟南芥PP2C基因家族比对表明,A^I为2个物种共有的亚族,J亚族只存在于谷子基因组中,L亚族只存在于拟南芥中。将谷子A亚族的10个成员命名为SiPP2CA1-10。基因表达谱分析表明,A亚族基因不同程度受ABA、干旱、高盐、低温和低氮诱导表达,其中,SiPP2CA6、SiPP2CA8在5种处理下诱导表达量都高。对10个A亚族成员的启动子分析发现,在这些基因的启动子序列中含有多种参与逆境胁迫应答的顺式作用元件,其中,SiPP2CA5、SiPP2CA6、SiPP2CA7、SiPP2CA8的启动子中含有参与低氮胁迫响应的元件。进一步研究发现,SiPP2CA8主要在根部表达,且在低氮胁迫下一直有较高的表达水平。亚细胞定位结果显示SiPP2CA8定位在细胞膜、细胞质、细胞核中;双分子荧光互补试验(BiFC)结果表明,SiPP2CA8与一个ABA受体类似蛋白SiRCAR3(基因号为Si018317m.g)在细胞膜、细胞质及细胞核上互作,表明SiPP2CA8在谷子中可能参与ABA信号传导过程。
