Interferon-γ decreases ATP-binding cassette subfamily G member 1-mediated cholesterol efflux through small ubiquitin-like modifier/ubiquitin-dependent liver X receptor-α degradation in macrophages
Interferon-γ decreases ATP-binding cassette subfamily G member 1-mediated cholesterol efflux through small ubiquitin-like modifier/ubiquitin-dependent liver X receptor-α degradation in macrophages
复制标题
干扰素-γ 通过巨噬细胞中的小型泛素样修饰剂/泛素依赖性肝脏 X 受体-α 降解，减少 ATP 结合盒亚家族 G 成员 1 介导的胆固醇流出
DOI：
10.1002/bab.2063
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发表时间：
2020-12-18
影响因子：
2.8
通讯作者：
Zhou, Juan
中科院分区：
文献类型：
--
作者：
Dong, Mengya;Zhang, Yan;Zhou, Juan
干扰素-γ对胆固醇蓄积和泡沫细胞发育的影响尚不清楚。在本研究中，我们发现干扰素-γ通过巨噬细胞中的泛素-蛋白酶体系统促进肝X受体(LXR)-α的降解。这一过程依赖于其与磷酸化信号转导和转录激活剂1(p-STAT1)和活化信号转导蛋白抑制物1(PIAS1)的相互作用，因为氟达拉滨和PIAS1 shRNA都能逆转干扰素-γ诱导的LXR-α蛋白表达的下降。此外，干扰素-γ还能增强泛素结合酶9(UBC9)、小泛素样修饰物(SUMO)-1和SUMO-2/3与LXR-α的相互作用。此外，针对它们的shRNA处理不仅减少了LXR-α的多泛素化，而且逆转了干扰素-γ诱导的LXR-α表达的下降。由于K22R和K326R突变抑制了干扰素诱导的巨噬细胞中LXR-α的多泛素化和降解，因此LXR-α上两个特异的苏莫化位点K22和K326对于其诱导的多泛素化是必不可少的。此外，K22R或K326R突变几乎完全恢复了干扰素-γ处理的巨噬细胞中ATP结合盒G成员1(Abcg1)介导的胆固醇外流。综上所述，这些发现表明，干扰素-γ通过泛素依赖途径促进LXR-α的降解，该途径可能抑制Abcg1介导的胆固醇从巨噬细胞流出，促进动脉粥样硬化的发展。
The effects of interferon-gamma (IFN-gamma) on cholesterol accumulation and the development of foam cells are still unclear. In the present study, we found that IFN-gamma promoted liver X receptor (LXR)-alpha degradation through the ubiquitin-proteasome system in macrophages. The process was dependent on its interactions with phosphorylated signal transducer and activator of transcription 1 (p-STAT1) and protein inhibitor of activated STAT 1 (PIAS1) because both fludarabine and PIAS1 shRNA reversed the decrease in LXR-alpha protein expression induced by IFN-gamma. Additionally, IFN-gamma enhanced the interactions of ubiquitin-conjugating enzyme 9 (UBC9), small ubiquitin-like modifier (SUMO)-1 and SUMO-2/3 with LXR-alpha. Moreover, treatment with shRNA specific for them not only reduced LXR-alpha polyubiquitination but also reversed the IFN-gamma-induced decrease in its expression. Two specific sumoylation sites in LXR-alpha, K22 and K326, were indispensable for its IFN-gamma-induced polyubiquitination because the K22R and K326R mutations inhibited the polyubiquitination and degradation of LXR-alpha in IFN-gamma-treated macrophages. In addition, K22R or K326R mutation almost completely restored ATP-binding cassette subfamily G member 1 (ABCG1)-mediated cholesterol efflux in IFN-gamma-treated macrophages. Taken together, these findings indicate that IFN-gamma promotes LXR-alpha degradation through a SUMO-ubiquitin-dependent pathway, which may inhibit cholesterol efflux mediated by ABCG1 from macrophages and promote the development of atherosclerosis.