HDAC6/aggresome processing pathway importance for inflammasome formation is context dependent.
HDAC6/aggresome processing pathway importance for inflammasome formation is context dependent.
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HDAC6/聚集体加工途径对炎症小体形成的重要性取决于环境。
DOI：
10.1101/2023.08.15.553363
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Matthias,Patrick
中科院分区：
文献类型：
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作者：
Wang,Longlong;Unterreiner,Adeline;Kapetanovic,Ronan;Aslani,Selma;Xiong,Yuan;Donovan,KatherineA;Farady,ChristopherJ;Fischer,EricS;Bornancin,Frédéric;Matthias,Patrick
炎性小体是一种大型多蛋白复合物，在细胞质中组装以响应应激或病原体感染。其主要功能是保护细胞并促进促炎细胞因子的分泌，包括 IL-1β 和 IL-18。先前的研究表明，在永生化骨髓源性巨噬细胞 (iBMDM) 中，炎症小体的组装依赖于脱乙酰酶 HDAC6 和聚集体加工途径 (APP)，这是一种参与处理错误折叠蛋白的细胞途径。在这里，我们使用来自 HDAC6 被消除或受损的小鼠的原代 BMDM，发现炎性体激活基本上是正常的。我们还使用表达合成蛋白的人外周血单核细胞和单核细胞系来阻断 HDAC6-泛素相互作用并损害 APP，发现炎症小体激活受到中度影响。最后，我们使用了一种新型 HDAC6 降解剂，结果表明，在 HDAC6 耗尽的人巨噬细胞系中，炎症小体激活部分受损。因此，我们的结果表明 HDAC6 在炎症小体激活中的重要性是依赖于环境的。
The inflammasome is a large multiprotein complex that assembles in the cell cytoplasm in response to stress or pathogenic infection. Its primary function is to defend the cell and promote the secretion of pro-inflammatory cytokines, including IL-1β and IL-18. Previous research has shown that in immortalized bone marrow-derived macrophages (iBMDMs) inflammasome assembly is dependent on the deacetylase HDAC6 and the aggresome processing pathway (APP), a cellular pathway involved in the disposal of misfolded proteins. Here we used primary BMDMs from mice in which HDAC6 is ablated or impaired and found that inflammasome activation was largely normal. We also used human peripheral blood mononuclear cells and monocyte cell lines expressing a synthetic protein blocking the HDAC6-ubiquitin interaction and impairing the APP and found that inflammasome activation was moderately affected. Finally, we used a novel HDAC6 degrader and showed that inflammasome activation was partially impaired in human macrophage cell lines with depleted HDAC6. Our results therefore show that HDAC6 importance in inflammasome activation is context-dependent.