Int J Biol Sci 2020; 16(15):2974-2988. doi:10.7150/ijbs.50186

Research Paper

The small molecule PSSM0332 disassociates the CRL4ADCAF8 E3 ligase complex to decrease the ubiquitination of NcoR1 and inhibit the inflammatory response in a mouse sepsis-induced myocardial dysfunction model

Qingyun Peng1, Huifen Xu1, Mingbing Xiao2✉, Linhua Wang1✉

1. Department of Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China.
2. Department of Gastroenterology and Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China.

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Citation:
Peng Q, Xu H, Xiao M, Wang L. The small molecule PSSM0332 disassociates the CRL4ADCAF8 E3 ligase complex to decrease the ubiquitination of NcoR1 and inhibit the inflammatory response in a mouse sepsis-induced myocardial dysfunction model. Int J Biol Sci 2020; 16(15):2974-2988. doi:10.7150/ijbs.50186. Available from http://www.ijbs.com/v16p2974.htm

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Abstract

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 CRL4ADCAF8, 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 HMGB1. Mature HMGB1 functioned as an effector to induce the expression of proinflammatory cytokines, causing inflammation and resulting in SIMD pathology. Using an in vitro 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 CRL4ADCAF8 E3 ligase is critical for the initiation of SIMD by regulating the expression of HMGB1 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.

Keywords: SIMD, CUL4A, RBX1, NcoR1, HMGB1, PSSM0332