Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion
Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion
复制标题
DOI：
10.1038/s41590-022-01255-6
复制
发表时间：
2022-07-06
影响因子：
30.5
通讯作者：
Sun, Bing
中科院分区：
文献类型：
--
作者：
Chen, Wen;Chen, Shuangfeng;Sun, Bing
Sun等报道白细胞介素-33（IL-33）的分泌依赖于gasdermin D的p40 N端片段，其产生不依赖于炎症性caspase-1和caspase-11。然而，过敏原暴露后IL-33分泌的分子机制尚不清楚。在这里，我们发现两个细胞事件是暴露于过敏原后IL-33分泌的基础。首先，过敏原激活的应激颗粒组装许可IL-33的核质转运，但不是IL-33的分泌。第二，新形式的鼠氨基末端p40片段gasdermin D（Gsdmd），其产生是独立的炎症半胱天冬酶-1和半胱天冬酶-11，占主导地位的细胞溶质分泌IL-33通过在细胞膜中形成孔。阻断应激颗粒的组装或通过氨基酸残基309-313的突变（ELRQQ）消除p40的产生可以有效地阻止小鼠上皮细胞中IL-33的释放。我们的研究结果表明，靶向应激颗粒分解和Gsdmd片段化可以减少IL-33依赖性过敏性气道炎症。
Sun and colleagues describe that the secretion of interleukin-33 is dependent on a p40 N-terminal fragment of gasdermin D, whose generation is independent of inflammatory caspase-1 and caspase-11.Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.