Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling

Yibo Zuo, Qian Feng, Lincong Jin, Fan Huang, Ying Miao, Jin Liu, Ying Xu, Xiangjie Chen, Hongguang Zhang, Tingting Guo, Yukang Yuan, Liting Zhang, Jun Wang and Hui Zheng ()
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Yibo Zuo: Soochow University
Qian Feng: Soochow University
Lincong Jin: Soochow University
Fan Huang: Soochow University
Ying Miao: Soochow University
Jin Liu: Soochow University
Ying Xu: the First Affiliated Hospital of Soochow University, Soochow University
Xiangjie Chen: Soochow University
Hongguang Zhang: Soochow University
Tingting Guo: Soochow University
Yukang Yuan: Soochow University
Liting Zhang: Soochow University
Jun Wang: the First Affiliated Hospital of Soochow University, Soochow University
Hui Zheng: Soochow University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14948-z

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