The Type I Interferon-IRF7 Axis Mediates Transcriptional Expression of Usp25 Gene

Abstract

Viral infection or lipopolysaccharide (LPS) treatment inducesexpression of a large array of genes, the products of which play a critical role in host antipathogen immunity and inflammation. We have previously reported that the expression of ubiquitinspecific protease 25 (USP25) is significantly up-regulated after viral infection or LPS treatment, and this is essential for innate immune signaling. However, the mechanism behind this phenomenon is unclear. In this study, we found that viral infectioninduced up-regulation of Usp25 is diminished in cells lacking interferon regulatory factor 7 (IRF7) or interferon ␣ receptor 1 (IFNAR1) but not p65. Sendai virus-or type I interferon-induced up-regulation of Usp25 requires de novo protein synthesis of IRF7. Furthermore, IRF7 directly binds to the two conserved IRF binding sites on the USP25 promoter to drive transcription of Usp25, and mutation of these two sites abolished Sendai virus-induced IRF7-mediated activation of the USP25 promoter. Our study has uncovered a previously unknown mechanism by which viral infection or LPS induces up-regulation of USP25.Host pattern recognition receptors recognize pathogen-associated molecular patterns and initiate a series of signaling cascades that lead to activation of transcription factors including NF-B and interferon regulatory factor 3 (IRF3) 2 (1-3). It has been well documented that activation of NF-B (p65/p50 heterodimer) is dependent on inhibitors of B kinase (IKK) complex (IKK␣/␤/␥)-mediated phosphorylation and degradation of IB␣, whereas activation of IRF3 requires phosphorylation by TBK1 or IKK⑀ (4 -9). The activated NF-B and IRF3 enter into nucleus, bind to the conserved B or IRF binding sites of promoters, and recruit co-activators to activate the transcription of target genes.Viral nucleic acid and lipopolysaccharide (LPS) of Gramnegative bacteria are two common pathogen-associated molecular patterns that trigger signaling cascades to activate NF-B and IRF3 and induce the production of type I interferons (IFNs) (3, 10). Type I IFNs further induce the expression of hundreds of downstream genes in an autocrine or paracrine manner, and the products of these genes including interferon-induced GTPbinding protein (Mx), 2Ј-5Ј-oligoadenylate synthase (OAS), double-stranded RNA-activated protein kinase (PKR), ISG56, and ISG15 orchestrate inhibition of pathogen replication and spread and promote apoptosis and clearance of the infected cells (11). In addition to the direct effect on innate immune cells for antipathogen responses, type I IFNs also regulate adaptive immunity including T cell activation and differentiation and antitumor immunity (12, 13).The type I IFN family is composed of 13 functional IFNA genes in humans (14 in mice), a single IFNB gene, and others. The IFN␣ family shares 80% sequence homology among them, whereas the homology between various IFN␣ and IFN␤ is 30% (14, 15). However, all the type I IFNs bind to the same receptors, IFNAR1 and IFNAR2, with affinities varying from picomolar to micromolar orders to re...

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