Department of Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China.
Department of Gastroenterology and Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China.
Int J Biol Sci. 2020 Sep 19;16(15):2974-2988. doi: 10.7150/ijbs.50186. eCollection 2020.
Sepsis-induced myocardial dysfunction (SIMD) is a life-threatening complication caused by inflammation, but how it is initiated is still unclear. Several studies have shown that extracellular high mobility group box 1 (HMGB1), an important cytokine triggering inflammation, is overexpressed during the pathogenesis of SIMD, but the underlying mechanism regarding its overexpression is still unknown. Herein, we discovered that CUL4A (cullin 4A) assembled an E3 ligase complex with RBX1 (ring-box 1), DDB1 (DNA damage-binding protein 1), and DCAF8 (DDB1 and CUL4 associated factor 8), termed CRL4A, which ubiquitinated and degraded NcoR1 (nuclear receptor corepressor 1) in an LPS-induced SIMD mouse model. The degradation of NcoR1 failed to form a complex with the SP1 transcription factor, leading to the upregulation of . Mature HMGB1 functioned as an effector to induce the expression of proinflammatory cytokines, causing inflammation and resulting in SIMD pathology. Using an AlphaScreen technology, we identified three small molecules that could inhibit the CUL4A-RBX1 interaction. Of them, PSSM0332 showed the strongest ability to inhibit the ubiquitination of NcoR1, and its administration in SIMD mice exhibited promising effects on decreasing the inflammatory response. Collectively, our results reveal that the CRL4A E3 ligase is critical for the initiation of SIMD by regulating the expression of and proinflammatory cytokines. Our results suggest that PSSM0332 is a promising candidate to inhibit the inflammatory response in the pathogenesis of SIMD, which will provide a new option for the therapy of SIMD.
脓毒症诱导性心肌功能障碍（SIMD）是一种由炎症引起的危及生命的并发症，但它是如何引发的仍不清楚。几项研究表明，细胞外高迁移率族蛋白 1（HMGB1）是一种重要的炎症触发细胞因子，在 SIMD 的发病机制中过度表达，但关于其过度表达的潜在机制仍不清楚。在此，我们发现 CUL4A（cullin 4A）与 RBX1（ring-box 1）、DDB1（DNA 损伤结合蛋白 1）和 DCAF8（DDB1 和 CUL4 相关因子 8）组装成 E3 连接酶复合物，称为 CRL4A，该复合物可使 LPS 诱导的 SIMD 小鼠模型中的 NcoR1（核受体共抑制因子 1）泛素化和降解。NcoR1 降解后无法与 SP1 转录因子形成复合物，导致 上调。成熟的 HMGB1 作为效应物发挥作用，诱导促炎细胞因子的表达，引起炎症，导致 SIMD 病理。使用 AlphaScreen 技术，我们鉴定出三种可抑制 CUL4A-RBX1 相互作用的小分子。其中，PSSM0332 显示出最强的抑制 NcoR1 泛素化的能力，其在 SIMD 小鼠中的给药对降低炎症反应表现出良好的效果。总之，我们的研究结果揭示了 CRL4A E3 连接酶通过调节 的表达和促炎细胞因子在 SIMD 的发病机制中起着至关重要的作用。我们的研究结果表明，PSSM0332 是抑制 SIMD 发病机制中炎症反应的有前途的候选药物，为 SIMD 的治疗提供了新的选择。
