SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways

Shuliang Chen; Serena Bonifati; Zhihua Qin; Corine St Gelais; Karthik M Kodigepalli; Bradley S Barrett; Sun Hee Kim; Jenna M Antonucci; Katherine J Ladner; Olga Buzovetsky; Kirsten M Knecht; Yong Xiong; Jacob S Yount; Denis C Guttridge; Mario L Santiago; Li Wu

doi:10.1073/pnas.1801213115

Back

SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways

Journal article

Open access

Peer reviewed

SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways

Shuliang Chen, Serena Bonifati, Zhihua Qin, Corine St Gelais, Karthik M Kodigepalli, Bradley S Barrett, Sun Hee Kim, Jenna M Antonucci, Katherine J Ladner, Olga Buzovetsky, …

Proceedings of the National Academy of Sciences - PNAS, Vol.115(16), pp.E3798-E3807

04/17/2018

DOI: 10.1073/pnas.1801213115

PMCID: PMC5910870

PMID: 29610295

Files and links (1)

url

https://doi.org/10.1073/pnas.1801213115View

Published (Version of record) Open Access

Abstract

Sterile alpha motif and HD-domain–containing protein 1 (SAMHD1) blocks replication of retroviruses and certain DNA viruses by reducing the intracellular dNTP pool. SAMHD1 has been suggested to down-regulate IFN and inflammatory responses to viral infections, although the functions and mechanisms of SAMHD1 in modulating innate immunity remain unclear. Here, we show that SAMHD1 suppresses the innate immune responses to viral infections and inflammatory stimuli by inhibiting nuclear factor-κB (NF-κB) activation and type I interferon (IFN-I) induction. Compared with control cells, infection of SAMHD1-silenced human monocytic cells or primary macrophages with Sendai virus (SeV) or HIV-1, or treatment with inflammatory stimuli, induces significantly higher levels of NF-κB activation and IFN-I induction. Exogenous SAMHD1 expression in cells or SAMHD1 reconstitution in knockout cells suppresses NF-κB activation and IFN-I induction by SeV infection or inflammatory stimuli. Mechanistically, SAMHD1 inhibits NF-κB activation by interacting with NF-κB1/2 and reducing phosphorylation of the NF-κB inhibitory protein IκBα. SAMHD1 also interacts with the inhibitor-κB kinase ε (IKKε) and IFN regulatory factor 7 (IRF7), leading to the suppression of the IFN-I induction pathway by reducing IKKε-mediated IRF7 phosphorylation. Interactions of endogenous SAMHD1 with NF-κB and IFN-I pathway proteins were validated in human monocytic cells and primary macrophages. Comparing splenocytes from SAMHD1 knockout and heterozygous mice, we further confirmed SAMHD1-mediated suppression of NF-κB activation, suggesting an evolutionarily conserved property of SAMHD1. Our findings reveal functions of SAMHD1 in down-regulating innate immune responses to viral infections and inflammatory stimuli, highlighting the importance of SAMHD1 in modulating antiviral immunity.

Phosphorylation

HIV - physiology

Humans

Male

NF-kappa B - metabolism

Signal Transduction - immunology

Macrophages - virology

Interferon-alpha - genetics

I-kappa B Kinase - antagonists & inhibitors

HEK293 Cells

Macrophages - immunology

Sendai virus - physiology

Virus Diseases - immunology

Interferon-alpha - biosynthesis

Down-Regulation

Cells, Cultured

Gene Silencing

THP-1 Cells

Inflammation - immunology

Immunity, Innate

Gene Expression Regulation - drug effects

Animals

Recombinant Proteins - immunology

Interferon Regulatory Factor-7 - antagonists & inhibitors

NF-KappaB Inhibitor alpha - metabolism

SAM Domain and HD Domain-Containing Protein 1 - physiology

Mice

Protein Processing, Post-Translational

Details

Title: Subtitle: SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways
Creators: Shuliang Chen - School of Basic Medical Sciences, Wuhan University, 430071 Wuhan, People's Republic of China
Serena Bonifati - Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210
Zhihua Qin - Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210
Corine St Gelais - Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210
Karthik M Kodigepalli - Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210
Bradley S Barrett - Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045
Sun Hee Kim - Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210
Jenna M Antonucci - Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210
Katherine J Ladner - Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
Olga Buzovetsky - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520
Kirsten M Knecht - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520
Yong Xiong - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520
Jacob S Yount - Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210
Denis C Guttridge - Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
Mario L Santiago - Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045
Li Wu - Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.115(16), pp.E3798-E3807
DOI: 10.1073/pnas.1801213115
PMID: 29610295
PMCID: PMC5910870
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 1091-6490
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: P30 CA016058 / NCI NIH HHS R01 AI102778 / NIAID NIH HHS T32 GM008283 / NIGMS NIH HHS R01 AI116603 / NIAID NIH HHS R01 GM128212 / NIGMS NIH HHS R01 AI104483 / NIAID NIH HHS T32 GM007223 / NIGMS NIH HHS R01 AI120209 / NIAID NIH HHS R01 AI130110 / NIAID NIH HHS
Language: English
Date published: 04/17/2018
Academic Unit: Microbiology and Immunology
Record Identifier: 9984001227102771

Metrics

24 Record Views

113 Times Cited - Web of Science