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Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling.
Nature Communications ( IF 14.7 ) Pub Date : 2020-03-02 , DOI: 10.1038/s41467-020-14948-z
Yibo Zuo 1, 2 , Qian Feng 1, 2 , Lincong Jin 1, 2 , Fan Huang 1, 2 , Ying Miao 1, 2 , Jin Liu 1, 2 , Ying Xu 3 , Xiangjie Chen 1, 2 , Hongguang Zhang 1, 2 , Tingting Guo 1, 2 , Yukang Yuan 1, 2 , Liting Zhang 1, 2 , Jun Wang 3 , Hui Zheng 1, 2
Nature Communications ( IF 14.7 ) Pub Date : 2020-03-02 , DOI: 10.1038/s41467-020-14948-z
Yibo Zuo 1, 2 , Qian Feng 1, 2 , Lincong Jin 1, 2 , Fan Huang 1, 2 , Ying Miao 1, 2 , Jin Liu 1, 2 , Ying Xu 3 , Xiangjie Chen 1, 2 , Hongguang Zhang 1, 2 , Tingting Guo 1, 2 , Yukang Yuan 1, 2 , Liting Zhang 1, 2 , Jun Wang 3 , Hui Zheng 1, 2
Affiliation
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Linear ubiquitination is a critical regulator of inflammatory signaling pathways. However, linearly ubiquitinated substrates and the biological significance of linear ubiquitination is incompletely understood. Here, we show that STAT1 has linear ubiquitination at Lys511 and Lys652 residues in intact cells, which inhibits STAT1 binding to the type-I interferon receptor IFNAR2, thereby restricting STAT1 activation and resulting in type-I interferon signaling homeostasis. Linear ubiquitination of STAT1 is removed rapidly by OTULIN upon type-I interferon stimulation, which facilitates activation of interferon-STAT1 signaling. Furthermore, viruses induce HOIP expression through the NF-κB pathway, which in turn increases linear ubiquitination of STAT1 and thereby inhibits interferon antiviral response. Consequently, HOIL-1L heterozygous mice have active STAT1 signaling and enhanced responses to type-I interferons. These findings demonstrate a linear ubiquitination-mediated switch between homeostasis and activation of type-I interferon signaling, and suggest potential strategies for clinical antiviral therapy.
中文翻译：
STAT1的线性泛素化的调控控制抗病毒干扰素信号传导。
线性泛素化是炎症信号通路的关键调节因子。但是，线性泛素化的底物和线性泛素化的生物学意义尚不完全清楚。在这里，我们显示STAT1在完整细胞中的Lys511和Lys652残基处具有线性泛素化作用，从而抑制STAT1与I型干扰素受体IFNAR2的结合，从而限制STAT1的激活并导致I型干扰素信号的稳态。STAT1的线性泛素化作用在I型干扰素刺激下被OTULIN快速去除，从而促进了STAT1信号传导的激活。此外，病毒通过NF-κB途径诱导HOIP表达，继而增加STAT1的线性泛素化，从而抑制干扰素抗病毒反应。所以，HOIL-1L杂合小鼠具有活跃的STAT1信号转导和对I型干扰素的增强反应。这些发现表明在稳态和I型干扰素信号传导激活之间存在线性泛素介导的转换，并提出了临床抗病毒治疗的潜在策略。
更新日期：2020-03-02
中文翻译：
STAT1的线性泛素化的调控控制抗病毒干扰素信号传导。
线性泛素化是炎症信号通路的关键调节因子。但是，线性泛素化的底物和线性泛素化的生物学意义尚不完全清楚。在这里，我们显示STAT1在完整细胞中的Lys511和Lys652残基处具有线性泛素化作用，从而抑制STAT1与I型干扰素受体IFNAR2的结合，从而限制STAT1的激活并导致I型干扰素信号的稳态。STAT1的线性泛素化作用在I型干扰素刺激下被OTULIN快速去除，从而促进了STAT1信号传导的激活。此外，病毒通过NF-κB途径诱导HOIP表达，继而增加STAT1的线性泛素化，从而抑制干扰素抗病毒反应。所以，HOIL-1L杂合小鼠具有活跃的STAT1信号转导和对I型干扰素的增强反应。这些发现表明在稳态和I型干扰素信号传导激活之间存在线性泛素介导的转换，并提出了临床抗病毒治疗的潜在策略。
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