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The classical NLRP3 inflammasome controls FADD unconventional secretion through microvesicle shedding.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-02-25 , DOI: 10.1038/s41419-019-1412-9
Sara Mouasni 1, 2, 3, 4 , Virginie Gonzalez 1, 2, 3, 4 , Alain Schmitt 2, 3, 4, 5 , Evangeline Bennana 2, 3, 4, 6 , François Guillonneau 2, 3, 4, 6 , Sylvie Mistou 1, 2, 3, 4 , Jérôme Avouac 1, 2, 3, 4, 7 , Hang Korng Ea 8, 9, 10 , Valérie Devauchelle 11 , Jacques-Eric Gottenberg 12 , Gilles Chiocchia 13, 14 , Léa Tourneur 1, 2, 3, 4
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-02-25 , DOI: 10.1038/s41419-019-1412-9
Sara Mouasni 1, 2, 3, 4 , Virginie Gonzalez 1, 2, 3, 4 , Alain Schmitt 2, 3, 4, 5 , Evangeline Bennana 2, 3, 4, 6 , François Guillonneau 2, 3, 4, 6 , Sylvie Mistou 1, 2, 3, 4 , Jérôme Avouac 1, 2, 3, 4, 7 , Hang Korng Ea 8, 9, 10 , Valérie Devauchelle 11 , Jacques-Eric Gottenberg 12 , Gilles Chiocchia 13, 14 , Léa Tourneur 1, 2, 3, 4
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Fas-associated death domain (FADD) is a key adaptor molecule involved in numerous physiological processes including cell death, proliferation, innate immunity and inflammation. Therefore, changes in FADD expression have dramatic cellular consequences. In mice and humans, FADD regulation can occur through protein secretion. However, the molecular mechanisms accounting for human FADD secretion were still unknown. Here we report that canonical, non-canonical, but not alternative, NLRP3 inflammasome activation in human monocytes/macrophages induced FADD secretion. NLRP3 inflammasome activation by the bacterial toxin nigericin led to the proinflammatory interleukin-1β (IL-1β) release and to the induction of cell death by pyroptosis. However, we showed that FADD secretion could occur in absence of increased IL-1β release and pyroptosis and, reciprocally, that IL-1β release and pyroptosis could occur in absence of FADD secretion. Especially, FADD, but not IL-1β, secretion following NLRP3 inflammasome activation required extracellular glucose. Thus, FADD secretion was an active process distinct from unspecific release of proteins during pyroptosis. This FADD secretion process required K+ efflux, NLRP3 sensor, ASC adaptor and CASPASE-1 molecule. Moreover, we identified FADD as a leaderless protein unconventionally secreted through microvesicle shedding, but not exosome release. Finally, we established human soluble FADD as a new marker of joint inflammation in gout and rheumatoid arthritis, two rheumatic diseases involving the NLRP3 inflammasome. Whether soluble FADD could be an actor in these diseases remains to be determined. Nevertheless, our results advance our understanding of the mechanisms contributing to the regulation of the FADD protein expression in human cells.
中文翻译：
经典的NLRP3炎症小体通过微泡脱落控制FADD非常规分泌。
Fas相关死亡域（FADD）是关键的衔接子分子，参与许多生理过程，包括细胞死亡，增殖，先天免疫和炎症。因此，FADD表达的变化具有戏剧性的细胞后果。在小鼠和人类中，FADD调节可通过蛋白质分泌发生。但是，尚不清楚人类FADD分泌的分子机制。在这里，我们报告人单核细胞/巨噬细胞中的规范性，非规范性但非替代性的NLRP3炎性小体激活诱导了FADD分泌。细菌毒素尼日利亚菌素激活的NLRP3炎性体导致促炎性白介素1β（IL-1β）释放，并导致细胞凋亡引起的细胞凋亡。但是，我们发现FADD分泌可能会在没有增加IL-1β释放和凋亡的情况下发生，反之，在没有FADD分泌的情况下可能发生IL-1β释放和细胞凋亡。特别是，NLRP3炎性小体激活后，FADD分泌但不是IL-1β分泌，需要细胞外葡萄糖。因此，FADD分泌是一个活跃的过程，不同于在焦磷酸化过程中蛋白质的非特异性释放。FADD分泌过程需要K +外排，NLRP3传感器，ASC衔接子和CASPASE-1分子。此外，我们将FADD确定为通过非微囊脱落而不是外泌体释放非常规方式分泌的无前导蛋白。最后，我们建立了人类可溶性FADD作为痛风和类风湿关节炎（两种涉及NLRP3炎性体的风湿病）关节炎症的新标志。可溶性FADD是否可能是这些疾病的参与者，尚待确定。尽管如此，
更新日期：2019-02-25
中文翻译：
经典的NLRP3炎症小体通过微泡脱落控制FADD非常规分泌。
Fas相关死亡域（FADD）是关键的衔接子分子，参与许多生理过程，包括细胞死亡，增殖，先天免疫和炎症。因此，FADD表达的变化具有戏剧性的细胞后果。在小鼠和人类中，FADD调节可通过蛋白质分泌发生。但是，尚不清楚人类FADD分泌的分子机制。在这里，我们报告人单核细胞/巨噬细胞中的规范性，非规范性但非替代性的NLRP3炎性小体激活诱导了FADD分泌。细菌毒素尼日利亚菌素激活的NLRP3炎性体导致促炎性白介素1β（IL-1β）释放，并导致细胞凋亡引起的细胞凋亡。但是，我们发现FADD分泌可能会在没有增加IL-1β释放和凋亡的情况下发生，反之，在没有FADD分泌的情况下可能发生IL-1β释放和细胞凋亡。特别是，NLRP3炎性小体激活后，FADD分泌但不是IL-1β分泌，需要细胞外葡萄糖。因此，FADD分泌是一个活跃的过程，不同于在焦磷酸化过程中蛋白质的非特异性释放。FADD分泌过程需要K +外排，NLRP3传感器，ASC衔接子和CASPASE-1分子。此外，我们将FADD确定为通过非微囊脱落而不是外泌体释放非常规方式分泌的无前导蛋白。最后，我们建立了人类可溶性FADD作为痛风和类风湿关节炎（两种涉及NLRP3炎性体的风湿病）关节炎症的新标志。可溶性FADD是否可能是这些疾病的参与者，尚待确定。尽管如此，
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