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

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 has linear ubiquitination at Lys511 and Lys652 residues in intact cells, which inhibits duanyu18131 binding to the type-I interferon receptor IFNAR2, thereby restricting duanyu18131 activation and resulting in type-I interferon signaling homeostasis. Linear ubiquitination of duanyu18131 is removed rapidly by OTULIN upon type-I interferon stimulation, which facilitates activation of signaling. Furthermore, viruses induce HOIP expression through the NF-κB pathway, which in turn increases linear ubiquitination of duanyu18131 and thereby inhibits interferon antiviral response. Consequently, HOIL-1L heterozygous mice have active duanyu18131 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.

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