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Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling.

Nature communications (2020-03-04)
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, Hui Zheng
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.

MATERIALS
Product Number
Brand
Product Description

Millipore
FLAG® Peptide, lyophilized powder
Sigma-Aldrich
Anti-Linear Ubiquitin Antibody, clone LUB9, clone LUB9, from mouse
Millipore
ANTI-FLAG® antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Millipore
Protein G Agarose, Fast Flow, Protein G Agarose, Fast Flow suitable for medium and low pressure chromatography of IgG from mouse, sheep, and rabbit, and for immunoprecipitations.