Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
Division of Nanotechnology Development, National Center for Nanoscience and Technology, Beijing, 100190, China.
Inflamm Res. 2024 Sep;73(9):1547-1564. doi: 10.1007/s00011-024-01913-5. Epub 2024 Jul 15.
Microglia, the main innate immune cells in the central nervous system, are key drivers of neuroinflammation, which plays a crucial role in the pathogenesis of neurodegenerative diseases. The Sin3/histone deacetylase (HDAC) complex, a highly conserved multiprotein co-repressor complex, primarily performs transcriptional repression via deacetylase activity; however, the function of SDS3, which maintains the integrity of the complex, in microglia remains unclear.
To uncover the regulatory role of the transcriptional co-repressor SDS3 in microglial inflammation, we used chromatin immunoprecipitation to identify SDS3 target genes and combined with transcriptomics and proteomics analysis to explore expression changes in cells following SDS3 knocking down. Subsequently, we validated our findings through experimental assays.
Our analysis revealed that SDS3 modulates the expression of the upstream kinase ASK1 of the p38 MAPK pathway, thus regulating the activation of signaling pathways and ultimately influencing inflammation.
Our findings provide important evidence of the contributions of SDS3 toward microglial inflammation and offer new insights into the regulatory mechanisms of microglial inflammatory responses.
小胶质细胞是中枢神经系统中的主要固有免疫细胞，是神经炎症的关键驱动因素，在神经退行性疾病的发病机制中起着至关重要的作用。Sin3/组蛋白去乙酰化酶（HDAC）复合物是一种高度保守的多蛋白共抑制复合物，主要通过去乙酰化酶活性进行转录抑制；然而，对于维持复合物完整性的 SDS3 在小胶质细胞中的功能尚不清楚。
为了揭示转录共抑制因子 SDS3 在小胶质细胞炎症中的调节作用，我们使用染色质免疫沉淀来鉴定 SDS3 的靶基因，并结合转录组学和蛋白质组学分析来探索 SDS3 敲低后细胞中的表达变化。随后，我们通过实验验证了我们的发现。
我们的分析表明，SDS3 调节 p38 MAPK 通路上游激酶 ASK1 的表达，从而调节信号通路的激活，最终影响炎症。
我们的发现为 SDS3 对小胶质细胞炎症的贡献提供了重要证据，并为小胶质细胞炎症反应的调节机制提供了新的见解。
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