SAMHD1 deficient human monocytes autonomously trigger type I interferon

• Type of Material: Article
• Authors: Alicia Martinez-Lopez, Albert Einstein College of Medicine; Marta Martin-Fernandez, Icahn School of Medicine at Mount Sinai; Sofija Buta, Icahn School of Medicine at Mount Sinai; Baek Kim, Emory University; Dusan Bogunovic, Icahn School of Medicine at Mount Sinai; Felipe Diaz-Griffero, Albert Einstein College of Medicine
• Language: English
• Date: 2018-09-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Ltd
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molimm.2018.08.005
• Title of Journal or Parent Work: Molecular Immunology
• ISSN: 0161-5890
• Volume: 101
• Start Page: 450
• End Page: 460
• Grant/Funding Information: The work was funded by an NIH grant (R01 GM123540) to F.D.-G and March of Dimes, R01AI127372, R21AI134366, R21AI129827 to D.B.
• Keywords: ANTIVIRAL RESPONSE; RESTRICTION FACTOR SAMHD1; RIBONUCLEASE-ACTIVITY; AUTOIMMUNE-DISEASE; ACID BINDING-PROTEIN; TBK1-IRF3; HIV-1 RESTRICTION; ISGs; NUCLEIC-ACIDS; Science & Technology; AGS; Immunology; IMMUNODEFICIENCY-VIRUS TYPE-1; SAMHD1; Biochemistry & Molecular Biology; IFN; Life Sciences & Biomedicine; POSITIVE FEEDBACK-REGULATION; AICARDI-GOUTIERES-SYNDROME
• Research Categories: Health Sciences, Immunology; Biology, Molecular

Abstract

Germline mutations in the human SAMHD1 gene cause the development of Aicardi-Goutières Syndrome (AGS), with a dominant feature being increased systemic type I interferon(IFN) production. Here we tested the state of type I IFN induction and response to, in SAMHD1 knockout (KO) human monocytic cells. SAMHD1 KO cells exhibited spontaneous transcription and translation of IFN-β and subsequent interferon-stimulated genes (ISGs) as compared to parental wild-type cells. This elevation of IFN-β and ISGs was abrogated via inhibition of the TBK1-IRF3 pathway in the SAMHD1 KO cells. In agreement, we found that SAMHD1 KO cells present high levels of phosphorylated TBK1 when compared to control cells. Moreover, addition of blocking antibody against type I IFN also reversed elevation of ISGs. These experiments suggested that SAMHD1 KO cells are persistently auto-stimulating the TBK1-IRF3 pathway, leading to an enhanced production of type I IFN and subsequent self-induction of ISGs.