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Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):E3798-E3807. doi: 10.1073/pnas.1801213115. Epub 2018 Apr 2.

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

Author information

1
Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210.
2
School of Basic Medical Sciences, Wuhan University, 430071 Wuhan, People's Republic of China.
3
Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045.
4
Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210.
5
Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210.
6
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520.
7
Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210.
8
Center for Retrovirus Research, Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210; wu.840@osu.edu.

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.

KEYWORDS:

NF-kB; SAMHD1; inflammatory stimuli; type I interferon; viral infection

PMID:
29610295
PMCID:
PMC5910870
DOI:
10.1073/pnas.1801213115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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