Li Meng, Hu Wei, Wang Ran, Li Zhaoyi, Yu Yue, Zhuo Yue, Zhang Yida, Wang Zhou, Qiu Yuanye, Chen Keyuan, Ding Qian, Qi Wei, Zhu Menglin, Zhu Yizhun
State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China.
Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
Antioxidants (Basel). 2022 Apr 7;11(4):732. doi: 10.3390/antiox11040732.
Histone deacetylase 6 (HDAC6) acts as a regulator of the nuclear factor kappa-B (NF-κB) signaling pathway by deacetylating the non-histone protein myeloid differentiation primary response 88 (MyD88) at lysine residues, which is an adapter protein for the Toll-like receptor (TLR) and interleukin (IL)-1β receptor. Over-activated immune responses, induced by infiltrated immune cells, excessively trigger the NF-κB signaling pathway in other effector cells and contribute to the development of rheumatoid arthritis (RA). It has also been reported that HDAC6 can promote the activation of the NF-κB signaling pathway. In the present study, we showed that HDAC6 protein level was increased in the synovium tissues of adjuvant-induced arthritis rats. In addition, hydrogen sulfide (HS) donor S-propargyl-cysteine (SPRC) can inhibit HDAC6 expression and alleviate inflammatory response in vivo. In vitro study revealed that HDAC6 overexpression activated the NF-κB signaling pathway by deacetylating MyD88. Meanwhile, sodium hydrosulfide (NaHS) or HDAC6 inhibitor tubastatin A (tubA) suppressed the pro-inflammatory function of HDAC6. Furthermore, the reduced expression of HDAC6 appeared to result from transcriptional inhibition by S-sulfhydrating specificity protein 1 (Sp1), which is a transcription factor of HDAC6. Our results demonstrate that Sp1 can regulate HDAC6 expression, and S-sulfhydration of Sp1 by antioxidant molecular HS ameliorates RA progression via the HDAC6/MyD88/NF-κB signaling pathway.
组蛋白去乙酰化酶6（HDAC6）通过使非组蛋白髓样分化初级反应蛋白88（MyD88）的赖氨酸残基去乙酰化，从而作为核因子κB（NF-κB）信号通路的调节因子，MyD88是Toll样受体（TLR）和白细胞介素（IL）-1β受体的衔接蛋白。浸润的免疫细胞诱导的过度激活的免疫反应，会过度触发其他效应细胞中的NF-κB信号通路，并促进类风湿性关节炎（RA）的发展。也有报道称HDAC6可促进NF-κB信号通路的激活。在本研究中，我们发现佐剂诱导的关节炎大鼠滑膜组织中HDAC6蛋白水平升高。此外，硫化氢（HS）供体S-炔丙基半胱氨酸（SPRC）可抑制HDAC6表达并减轻体内炎症反应。体外研究表明，HDAC6过表达通过使MyD88去乙酰化激活NF-κB信号通路。同时，硫氢化钠（NaHS）或HDAC6抑制剂tubastatin A（tubA）抑制了HDAC6的促炎功能。此外，HDAC6表达降低似乎是由于HDAC6的转录因子特异性蛋白1（Sp1）的S-巯基化导致的转录抑制。我们的结果表明，Sp1可调节HDAC6表达，抗氧化分子HS对Sp1的S-巯基化通过HDAC6/MyD88/NF-κB信号通路改善RA进展。
