SERPINB1-mediated checkpoint of inflammatory caspase activation
SERPINB1-mediated checkpoint of inflammatory caspase activation
复制标题
DOI：
10.1038/s41590-018-0303-z
复制
发表时间：
2019-03-01
影响因子：
30.5
通讯作者：
Jung, Jae U.
中科院分区：
文献类型：
--
作者：
Choi, Youn Jung;Kim, Stephanie;Jung, Jae U.
炎症性caspase(caspase-1、caspase-4、caspase-5和caspase-11，caspase-1/-4/-5/-11)介导宿主对微生物感染的防御，处理致炎细胞因子并触发下垂。但是，需要精确的检查点以防止其未经请求的激活。在这里，我们报告了丝氨酸B家族成员1(SerpinB1)通过抑制caspase招募结构域(CARD)寡聚和酶激活来限制这些caspase的活性。SerpinB1的反应中心环抑制中性粒细胞丝氨酸蛋白酶，其羧基末端的卡片结合基序抑制caspase-1/-4/-5/-11的激活。因此，serpinB1的敲除或缺失会导致caspase-1/-4/-5/-11的自发激活，细胞因子IL-1β的释放和下垂，导致与宠物店小鼠不卫生的共居后炎症加剧，并增强对内毒素或鲍曼不动杆菌诱导的内毒素血症的敏感性。我们的结果显示，serpinB1通过抑制中性粒细胞丝氨酸蛋白酶和炎性caspase，在基因和功能上可分离的方式，扮演着重要的炎症门卫的角色。
Inflammatory caspases (caspase-1, caspase-4, caspase-5 and caspase-11 (caspase-1/-4/-5/-11)) mediate host defense against microbial infections, processing pro-inflammatory cytokines and triggering pyroptosis. However, precise checkpoints are required to prevent their unsolicited activation. Here we report that serpin family B member 1 (SERPINB1) limited the activity of those caspases by suppressing their caspase-recruitment domain (CARD) oligomerization and enzymatic activation. While the reactive center loop of SERPINB1 inhibits neutrophil serine proteases, its carboxy-terminal CARD-binding motif restrained the activation of pro-caspase-1/-4/-5/-11. Consequently, knockdown or deletion of SERPINB1 prompted spontaneous activation of caspase-1/-4/-5/-11, release of the cytokine IL-1 beta and pyroptosis, inducing elevated inflammation after non-hygienic co-housing with pet-store mice and enhanced sensitivity to lipopolysaccharide- or Acinetobacter baumannii-induced endotoxemia. Our results reveal that SERPINB1 acts as a vital gatekeeper of inflammation by restraining neutrophil serine proteases and inflammatory caspases in a genetically and functionally separable manner.