小柯机器人

日本东京大学Toshiyuki Shimizu和Umeharu Ohto共同合作，近期取得重要工作进展。他们研究发现了硫氧还蛋白介导的NLRP1炎症小体抑制的结构基础。相关研究成果2023年9月13日在线发表于《自然》杂志上。

据介绍，炎性体传感器检测病原体和危险相关的分子模式并促进炎症和细胞焦亡。NLRP1是第一个被描述的炎症小体传感器，其过度激活与自身炎症性疾病和癌症有关。然而，NLRP1的激活和调节机制尚未明确阐明。

研究人员鉴定了普遍表达的内源性硫氧还蛋白（TRX）作为NLRP1的结合物和NLRP1炎症小体的抑制剂。人NLRP1的冷冻电镜结构显示NLRP1与草地贪夜蛾（Spodoptera frugiperda）TRX结合。NLRP1和人TRX的突变研究表明，氧化形式的TRX与NLRP1的核苷酸结合结构域亚结构域结合。这一观察结果强调了TRX的氧化还原活性半胱氨酸在NLRP1结合中的关键作用。细胞测定显示TRX抑制NLRP1炎症小体的激活，从而负调控NLRP1。

总之，这一数据确定TRX系统是先天免疫的内在检查点，并为未来针对该系统的NLRP1炎症小体激活的治疗干预提供了机会。

附：英文原文

Title: Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome

Author: Zhang, Zhikuan, Shibata, Takuma, Fujimura, Akiko, Kitaura, Jiro, Miyake, Kensuke, Ohto, Umeharu, Shimizu, Toshiyuki

Issue&Volume: 2023-09-13

Abstract: Inflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis1. NLRP1 was the first inflammasome sensor to be described, and its hyperactivation is linked to autoinflammatory disease and cancer2–6. However, the mechanism underlying the activation and regulation of NLRP1 has not been clearly elucidated4,7,8. Here we identify ubiquitously expressed endogenous thioredoxin (TRX) as a binder of NLRP1 and a suppressor of the NLRP1 inflammasome. The cryo-electron microscopy structure of human NLRP1 shows NLRP1 bound to Spodoptera frugiperda TRX. Mutagenesis studies of NLRP1 and human TRX show that TRX in the oxidized form binds to the nucleotide-binding domain subdomain of NLRP1. This observation highlights the crucial role of redox-active cysteines of TRX in NLRP1 binding. Cellular assays reveal that TRX suppresses NLRP1 inflammasome activation and thus negatively regulates NLRP1. Our data identify the TRX system as an intrinsic checkpoint for innate immunity and provide opportunities for future therapeutic intervention in NLRP1 inflammasome activation targeting this system. Structural and mutational studies and cellular assays show that the inflammasome sensor NLRP1 forms a complex with thioredoxin, which acts as a negative regulator of inflammasome activity.

DOI: 10.1038/s41586-023-06532-4

Source: https://www.nature.com/articles/s41586-023-06532-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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