研究发现细胞死亡与骨关节炎(osteoarthritis,OA)的发病机制密切相关,除了凋亡、铁死亡、焦亡以外,目前又发现了一种全新的由受体相互作用蛋白激酶1(receptor-interacting protein kinase 1,RIPK1)和受体相互作用蛋白激酶3(receptor-int...研究发现细胞死亡与骨关节炎(osteoarthritis,OA)的发病机制密切相关,除了凋亡、铁死亡、焦亡以外,目前又发现了一种全新的由受体相互作用蛋白激酶1(receptor-interacting protein kinase 1,RIPK1)和受体相互作用蛋白激酶3(receptor-interacting protein kinase 3,RIPK3)介导的细胞死亡方式——程序性坏死。作为一种新型的受调控的细胞死亡方式,细胞的程序性坏死已被证实在部分炎症性疾病中扮演着重要的角色,但其与OA的关系还不够明晰。本文通过对PubMed、Web of Science、中国知网数据库的检索结果进行分析,总结了程序性坏死的特征、分子机制及其与软骨细胞炎症的关系等,期望对阐明软骨细胞程序性坏死在OA疾病进程中的作用有所帮助。展开更多
Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response...Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFNstimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)pathway.However,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains unclear.Here,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation.RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral replication.RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type I IFNs.Conversely,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication.RIPK3^(-/-)mice also maintained a robust ability to clear HTNV with enhanced innate immune responses.Mechanistically,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase activity.Overall,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.展开更多
细胞程序性坏死是一种不依赖于Caspase、可调控的细胞死亡方式,参与多种疾病的病理过程,如病毒或病原菌感染、动脉硬化、心脏缺血再灌注和肿瘤等。受体相互作用蛋白激酶3(receptor-interacting protein kinase 3,RIPK3)是细胞程序性坏...细胞程序性坏死是一种不依赖于Caspase、可调控的细胞死亡方式,参与多种疾病的病理过程,如病毒或病原菌感染、动脉硬化、心脏缺血再灌注和肿瘤等。受体相互作用蛋白激酶3(receptor-interacting protein kinase 3,RIPK3)是细胞程序性坏死的关键调控分子,可与受体相互作用蛋白激酶1(receptor-interacting protein kinase 1,RIPK1)形成坏死小体,激活混合谱系激酶结构域样蛋白(mixed lineage kinase domain-like pseudokinase,MLKL),导致细胞膜破裂和细胞死亡。近年来,越来越多研究发现RIPK3活性可受多种翻译后修饰如磷酸化、泛素化、糖基化和蛋白水解切割等调控。该文就RIPK3翻译后修饰在调控细胞程序性坏死信号转导中的作用进行综述,期望为靶向RIPK3的药物设计及细胞程序性坏死相关疾病的治疗提供理论依据。展开更多
文摘研究发现细胞死亡与骨关节炎(osteoarthritis,OA)的发病机制密切相关,除了凋亡、铁死亡、焦亡以外,目前又发现了一种全新的由受体相互作用蛋白激酶1(receptor-interacting protein kinase 1,RIPK1)和受体相互作用蛋白激酶3(receptor-interacting protein kinase 3,RIPK3)介导的细胞死亡方式——程序性坏死。作为一种新型的受调控的细胞死亡方式,细胞的程序性坏死已被证实在部分炎症性疾病中扮演着重要的角色,但其与OA的关系还不够明晰。本文通过对PubMed、Web of Science、中国知网数据库的检索结果进行分析,总结了程序性坏死的特征、分子机制及其与软骨细胞炎症的关系等,期望对阐明软骨细胞程序性坏死在OA疾病进程中的作用有所帮助。
基金This work was supported in whole or in part by the National Natural Science Foundation of China(82172272,31970148 and 82222367)the Key Research and Development Program of Shaanxi(2021ZDLSF01-05 and 2021ZDLSF01-02).
文摘Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFNstimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)pathway.However,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains unclear.Here,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation.RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral replication.RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type I IFNs.Conversely,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication.RIPK3^(-/-)mice also maintained a robust ability to clear HTNV with enhanced innate immune responses.Mechanistically,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase activity.Overall,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.
