A central role for PI3K-AKT signaling pathway in linking SAMHD1-deficiency to the type I interferon signature

• Type of Material: Article
• Authors: Changhoon Oh, Seoul National University; Jeongmin Ryoo, Seoul National University; Kiwon Park, Seoul National University; Baek Kim, Emory University; Michele B. Daly, Emory University; DongYeon Cho, Seoul National University; Kwangseog Ahn, Seoul National University
• Language: English
• Date: 2018-01-08
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2017
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-017-18308-8
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 8
• Start Page: 84
• End Page: 84
• Grant/Funding Information: This work was supported by the Samsung Science & Technology Foundation Grant (SSTF-BA1402-19) to K.A. and NIH GM104198 to B.K.
• Keywords: Autoimmunity; ACTIVATION; RESTRICTION FACTOR SAMHD1; MUTATIONS; HIV-1 RESTRICTION; Multidisciplinary Sciences; RECOGNITION; SYNDROME GENE; SINGLE-STRANDED RNA; Innate immunity; NUCLEASE ACTIVITY; Science & Technology; AICARDI-GOUTIERES-SYNDROME; ACID BINDING-PROTEIN; Science & Technology - Other Topics
• Research Categories: Biology, Genetics; Health Sciences, Immunology

Abstract

The autoimmune disorder Aicardi-Goutières syndrome (AGS) is characterized by a constitutive type I interferon response. SAMHD1 possesses both dNTPase and RNase activities and mutations in SAMHD1 cause AGS; however, how SAMHD1-deficiency causes the type I interferon response in patients with AGS remains unknown. Here, we show that endogenous RNA substrates accumulated in the absence of SAMHD1 act as a major immunogenic source for the type I interferon response. Reconstitution of SAMHD1-negative human cells with wild-type but not RNase-defective SAMHD1 abolishes spontaneous type I interferon induction. We further identify that the PI3K/AKT/IRF3 signaling pathway is essential for the type I interferon response in SAMHD1-deficient human monocytic cells. Treatment of PI3K or AKT inhibitors dramatically reduces the type I interferon signatures in SAMHD1-deficient cells. Moreover, SAMHD1/AKT1 double knockout relieves the type I interferon signatures to the levels observed for wild-type cells. Identification of AGS-related RNA sensing pathway provides critical insights into the molecular pathogenesis of the type I interferonopathies such as AGS and overlapping autoimmune disorders.