PMID- 37328105 OWN - NLM STAT- MEDLINE DCOM- 20230803 LR - 20240330 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 299 IP - 7 DP - 2023 Jul TI - SAMHD1 impairs type I interferon induction through the MAVS, IKKepsilon, and IRF7 signaling axis during viral infection. PG - 104925 LID - S0021-9258(23)01953-1 [pii] LID - 10.1016/j.jbc.2023.104925 [doi] LID - 104925 AB - Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) restricts human immunodeficiency virus type 1 (HIV-1) infection by reducing the intracellular dNTP pool. We have shown that SAMHD1 suppresses nuclear factor kappa-B activation and type I interferon (IFN-I) induction by viral infection and inflammatory stimuli. However, the mechanism by which SAMHD1 inhibits IFN-I remains unclear. Here, we show that SAMHD1 inhibits IFN-I activation induced by the mitochondrial antiviral-signaling protein (MAVS). SAMHD1 interacted with MAVS and suppressed MAVS aggregation in response to Sendai virus infection in human monocytic THP-1 cells. This resulted in increased phosphorylation of TANK binding kinase 1 (TBK1), inhibitor of nuclear factor kappa-B kinase epsilon (IKKepsilon), and IFN regulatory factor 3 (IRF3). SAMHD1 suppressed IFN-I activation induced by IKKepsilon and prevented IRF7 binding to the kinase domain of IKKepsilon. We found that SAMHD1 interaction with the inhibitory domain (ID) of IRF7 (IRF7-ID) was necessary and sufficient for SAMHD1 suppression of IRF7-mediated IFN-I activation in HEK293T cells. Computational docking and molecular dynamics simulations revealed possible binding sites between IRF7-ID and full-length SAMHD1. Individual substitution of F411, E416, or V460 in IRF7-ID significantly reduced IRF7 transactivation activity and SAMHD1 binding. Furthermore, we investigated the role of SAMHD1 inhibition of IRF7-mediated IFN-I induction during HIV-1 infection. We found that THP-1 cells lacking IRF7 expression had reduced HIV-1 infection and viral transcription compared to control cells, indicating a positive role of IRF7 in HIV-1 infection. Our findings suggest that SAMHD1 suppresses IFN-I induction through the MAVS, IKKepsilon, and IRF7 signaling axis. CI - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Espada, Constanza E AU - Espada CE AD - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. FAU - Sari, Levent AU - Sari L AD - Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. FAU - Cahill, Michael P AU - Cahill MP AD - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. FAU - Yang, Hua AU - Yang H AD - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. FAU - Phillips, Stacia AU - Phillips S AD - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. FAU - Martinez, Nicholas AU - Martinez N AD - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA. FAU - Kenney, Adam D AU - Kenney AD AD - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA. FAU - Yount, Jacob S AU - Yount JS AD - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA. FAU - Xiong, Yong AU - Xiong Y AD - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA. FAU - Lin, Milo M AU - Lin MM AD - Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Electronic address: Milo.Lin@UTSouthwestern.edu. FAU - Wu, Li AU - Wu L AD - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. Electronic address: li-wu@uiowa.edu. LA - eng GR - R01 AI141495/AI/NIAID NIH HHS/United States GR - R01 HL168501/HL/NHLBI NIH HHS/United States GR - R61 AI169659/AI/NIAID NIH HHS/United States GR - R01 HL154001/HL/NHLBI NIH HHS/United States GR - R21 AI170070/AI/NIAID NIH HHS/United States GR - T32 AI165391/AI/NIAID NIH HHS/United States GR - R01 AI130110/AI/NIAID NIH HHS/United States GR - R01 HL157215/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20230614 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - EC 2.7.11.10 (I-kappa B Kinase) RN - 0 (Interferon Regulatory Factor-3) RN - 0 (Interferon Regulatory Factor-7) RN - 0 (Interferon Type I) RN - EC 3.1.5.- (SAM Domain and HD Domain-Containing Protein 1) RN - EC 3.1.5.- (SAMHD1 protein, human) RN - 0 (MAVS protein, human) RN - 0 (IRF3 protein, human) RN - 0 (IRF7 protein, human) SB - IM MH - Humans MH - HEK293 Cells MH - I-kappa B Kinase/genetics/metabolism MH - Immunity, Innate MH - Interferon Regulatory Factor-3/metabolism MH - Interferon Regulatory Factor-7/genetics/metabolism MH - *Interferon Type I/metabolism MH - *SAM Domain and HD Domain-Containing Protein 1/metabolism MH - *HIV Infections/metabolism MH - Signal Transduction PMC - PMC10404699 OTO - NOTNLM OT - HIV-1 OT - IKKepsilon OT - IRF OT - MAVS OT - SAMHD1 OT - innate immunity OT - interferon OT - molecular docking COIS- Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. EDAT- 2023/06/17 05:11 MHDA- 2023/07/31 06:42 PMCR- 2023/06/14 CRDT- 2023/06/16 19:18 PHST- 2023/05/02 00:00 [received] PHST- 2023/06/06 00:00 [revised] PHST- 2023/06/07 00:00 [accepted] PHST- 2023/07/31 06:42 [medline] PHST- 2023/06/17 05:11 [pubmed] PHST- 2023/06/16 19:18 [entrez] PHST- 2023/06/14 00:00 [pmc-release] AID - S0021-9258(23)01953-1 [pii] AID - 104925 [pii] AID - 10.1016/j.jbc.2023.104925 [doi] PST - ppublish SO - J Biol Chem. 2023 Jul;299(7):104925. doi: 10.1016/j.jbc.2023.104925. Epub 2023 Jun 14.