Da Gula, Wang Junmin, Shang Jing, Xun Cuiping, Yu Yang, Wang Yong, Tie Ning, Li Hongbin
Department of Rheumatology and Immunology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
Inner Mongolia Key Laboratory for Pathogenesis and Diagnosis of Rheumatic and Autoimmune Diseases, Hohhot, China.
Cell Death Discov. 2024 Oct 5;10(1):429. doi: 10.1038/s41420-024-02194-x.
Type I interferon (IFN-I) plays a crucial role in the antiviral immune response and inflammatory autoimmune diseases by inducing the expression of IFN-stimulated genes (ISGs). Hence, the regulation of ISG expression is fundamental for maintaining immune homeostasis. In this study, we found that PCGF3 negatively regulates the antiviral response by suppressing the expression of ISGs. The deficiency of PCGF3 in innate immune cells results in an augmented expression of ISGs in response to IFN-I stimulation. Mechanistically, PCGF3 is recruited to interferon-stimulated response elements (ISREs) region in an IFN-dependent way, precluding STAT1 from binding to the ISG promoter and diminishing ISRE activity. Additionally, we observed a negative correlation between decreased PCGF3 expression and elevated ISG expression in peripheral blood mononuclear cells (PBMCs) of patients with dermatomyositis (DM). Our findings clarified the epigenetic regulatory role of PCGF3 in inhibiting the excessive expression of ISGs induced by IFN-I under pathological circumstances.
I型干扰素（IFN-I）通过诱导干扰素刺激基因（ISG）的表达，在抗病毒免疫反应和炎症性自身免疫疾病中发挥关键作用。因此，ISG表达的调控对于维持免疫稳态至关重要。在本研究中，我们发现PCGF3通过抑制ISG的表达来负向调节抗病毒反应。天然免疫细胞中PCGF3的缺陷导致在IFN-I刺激下ISG的表达增加。机制上，PCGF3以IFN依赖的方式被招募到干扰素刺激反应元件（ISRE）区域，阻止STAT1与ISG启动子结合并降低ISRE活性。此外，我们观察到皮肌炎（DM）患者外周血单个核细胞（PBMC）中PCGF3表达降低与ISG表达升高之间呈负相关。我们的研究结果阐明了PCGF3在病理情况下抑制IFN-I诱导的ISG过度表达的表观遗传调控作用。
