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NLRP3感知细胞内低钾会导致一种稳定的开放结构，从而促进炎性小体激活。

Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation.

作者信息

Tapia-Abellán Ana, Angosto-Bazarra Diego, Alarcón-Vila Cristina, Baños María C, Hafner-Bratkovič Iva, Oliva Baldomero, Pelegrín Pablo

机构信息

Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain.

Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.

出版信息

Sci Adv. 2021 Sep 17;7(38):eabf4468. doi: 10.1126/sciadv.abf4468. Epub 2021 Sep 15.

DOI:10.1126/sciadv.abf4468
PMID:34524838
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8443177/
Abstract

The NLRP3 inflammasome is activated by a wide range of stimuli and drives diverse inflammatory diseases. The decrease of intracellular K concentration is a minimal upstream signal to most of the NLRP3 activation models. Here, we found that cellular K efflux induces a stable structural change in the inactive NLRP3, promoting an open conformation as a step preceding activation. This conformational change is facilitated by the specific NLRP3 FISNA domain and a unique flexible linker sequence between the PYD and FISNA domains. This linker also facilitates the ensemble of NLRP3 into a seed structure for ASC oligomerization. The introduction of the NLRP3 PYD-linker-FISNA sequence into NLRP6 resulted in a chimeric receptor able to be activated by K efflux–specific NLRP3 activators and promoted an in vivo inflammatory response to uric acid crystals. Our results establish that the amino-terminal sequence between PYD and NACHT domain of NLRP3 is key for inflammasome activation.

摘要

NLRP3炎性小体可被多种刺激激活，并引发多种炎症性疾病。细胞内钾离子浓度降低是大多数NLRP3激活模型的最小上游信号。在此，我们发现细胞内钾外流会诱导无活性NLRP3发生稳定的结构变化，促进其形成开放构象，作为激活前的一个步骤。这种构象变化由特定的NLRP3 FISNA结构域以及PYD和FISNA结构域之间独特的柔性连接序列所促进。该连接序列还促进NLRP3聚集成ASC寡聚化的种子结构。将NLRP3的PYD-连接序列-FISNA序列引入NLRP6中，产生了一种嵌合受体，该受体能够被钾外流特异性NLRP3激活剂激活，并促进体内对尿酸晶体的炎症反应。我们的结果表明，NLRP3的PYD和NACHT结构域之间的氨基末端序列是炎性小体激活的关键。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d85/8443177/cbdac04a3a3d/sciadv.abf4468-f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d85/8443177/9e306a2a6742/sciadv.abf4468-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d85/8443177/cbdac04a3a3d/sciadv.abf4468-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d85/8443177/7c4ef4659bb7/sciadv.abf4468-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d85/8443177/9a0fb8ecfed5/sciadv.abf4468-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d85/8443177/892f98c73af4/sciadv.abf4468-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d85/8443177/942a1d0a9401/sciadv.abf4468-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d85/8443177/9e306a2a6742/sciadv.abf4468-f7.jpg
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本文引用的文献

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Cell Rep. 2020 Nov 17;33(7):108405. doi: 10.1016/j.celrep.2020.108405.
2
HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation.HDAC6 通过类似聚集物的机制介导 NLRP3 和 pyrin 炎症小体的激活。
Science. 2020 Sep 18;369(6510). doi: 10.1126/science.aas8995.
3
The gasdermins, a protein family executing cell death and inflammation.
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Int J Mol Sci. 2025 Aug 6;26(15):7624. doi: 10.3390/ijms26157624.
4
Mitigating organophosphate nerve agent, soman (GD), induced long-term neurotoxicity: Saracatinib, a Src Tyrosine Kinase inhibitor, as a potential countermeasure.减轻有机磷酸酯类神经毒剂梭曼（GD）所致的长期神经毒性：Src酪氨酸激酶抑制剂萨拉卡替尼作为一种潜在的应对措施。
J Neuroinflammation. 2025 Aug 5;22(1):199. doi: 10.1186/s12974-025-03520-5.
5
Mitigating Organophosphate Nerve Agent, Soman (GD)-Induced Long-Term Neurotoxicity: Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Potential Countermeasure.减轻有机磷酸酯类神经毒剂梭曼（GD）所致的长期神经毒性：Src酪氨酸激酶抑制剂萨拉卡替尼作为一种潜在的应对措施。
Res Sq. 2025 Jun 24:rs.3.rs-6674766. doi: 10.21203/rs.3.rs-6674766/v1.
6
Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of Sepsis.炎性小体与信号通路：脓毒症病理生理学的关键机制
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9
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