Journal Article

Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling

Zhang, Hongguang, Feng, Qian, Zhang, Liting, Liu, Jin, Yuan, Yukang, Zuo, Yibo, Wang, Jun, Jin, Lincong, Chen, Xiangjie, Miao, Ying, Guo, Tingting, Xu, Ying, Zheng, Hui, Huang, Fan

2020

Overview

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. LUBAC is involved in adding linear ubiquitin chains to important immune signaling proteins. Here the authors show that this mechanism is effective in inhibiting STAT1-mediated interferon signaling, and that the deubiquitinase OTULIN can remove these linear ubiquitins from STAT1 to reactivate this antiviral signaling pathway.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/21 / 13/89 / 14/19 / 38 / 38/109 / 38/90 / 631/250/127/1212 / 631/326/596/2558 / 631/80/458/582 / 64 / 64/60 / 82/58 / 82/80 / 82/83 / 96 / Activation / Animals / Antiviral agents / Antiviral drugs / Cell Line / Homeostasis / Host-Pathogen Interactions - physiology / Humanities and Social Sciences / Humans / Inflammation / Interferon / Interferon Type I - metabolism / Interferon Type I - pharmacology / Lysine - metabolism / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Mutant Strains / multidisciplinary / NF-κB protein / Receptor, Interferon alpha-beta - metabolism / Science / Science (multidisciplinary) / Signal transduction / Signal Transduction - drug effects / Signaling / Stat1 protein / STAT1 Transcription Factor - genetics / STAT1 Transcription Factor - metabolism / Substrates / Ubiquitin / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Ubiquitination