Department of Immunology, Institute for Immunobiology, Shanghai Medical College of Fudan University, Shanghai 200032, People's Republic of China.
J Immunol. 2013 Jul 1;191(1):464-71. doi: 10.4049/jimmunol.1203533. Epub 2013 May 31.
Tripartite motif (TRIM)22 plays an important role in IFN-mediated antiviral activity. We previously demonstrated that IFN regulatory factor (IRF)-1 was crucial for basal and IFN-induced TRIM22 transcription via binding to a novel cis-element named 5' extended IFN-stimulating response element. In this study, we investigated the role of histone deacetylase (HDAC) activity in TRIM22 induction by IFN-γ and its underlying mechanism. We found that the HDAC activity, especially that conferred by HDAC6, was required for IFN-γ-induced TRIM22 transcription. Importantly, inhibition of HDAC activity by trichostatin A (TSA) enhanced the hyperacetylation of heat shock protein (HSP)90 and suppressed its chaperone activity for IRF-1. Further study showed that TSA treatment promoted the proteasomal degradation of IRF-1 protein via enhancing the association of IRF-1 with the ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein. Moreover, carboxyl terminus of Hsc70-interacting protein was found to be involved in the TSA-mediated inhibitory effect on IFN-γ induction of TRIM22 as well as other IRF-1-dependent IFN-stimulated genes. This study may provide novel insight into the role of HDAC activity in the transcriptional control of IFN-stimulated gene induction.
三结构域蛋白 22（TRIM22）在 IFN 介导的抗病毒活性中发挥重要作用。我们之前的研究表明，干扰素调节因子（IRF）-1 通过与一个名为 5' 扩展 IFN 刺激反应元件的新顺式元件结合，对于基础和 IFN 诱导的 TRIM22 转录至关重要。在这项研究中，我们研究了组蛋白去乙酰化酶（HDAC）活性在 IFN-γ诱导 TRIM22 转录中的作用及其潜在机制。我们发现，HDAC 活性，特别是由 HDAC6 赋予的，是 IFN-γ诱导 TRIM22 转录所必需的。重要的是，用曲古抑菌素 A（TSA）抑制 HDAC 活性增强了热休克蛋白（HSP）90 的乙酰化，并抑制了其对 IRF-1 的伴侣活性。进一步的研究表明，TSA 处理通过增强 IRF-1 与泛素 E3 连接酶羧基末端 HSP70 相互作用蛋白的关联，促进了 IRF-1 蛋白的蛋白酶体降解。此外，还发现羧基末端 HSP70 相互作用蛋白参与了 TSA 介导的对 IFN-γ诱导的 TRIM22 以及其他 IRF-1 依赖性 IFN 刺激基因的抑制作用。这项研究可能为 HDAC 活性在 IFN 刺激基因诱导的转录控制中的作用提供新的见解。
