| First Author | Chen S | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 16 | Pages | E3798-E3807 |
| PubMed ID | 29610295 | Mgi Jnum | J:261389 |
| Mgi Id | MGI:6154432 | Doi | 10.1073/pnas.1801213115 |
| Citation | Chen S, et al. (2018) SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-kappaB and interferon pathways. Proc Natl Acad Sci U S A 115(16):E3798-E3807 |
| abstractText | 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-kappaB (NF-kappaB) 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-kappaB activation and IFN-I induction. Exogenous SAMHD1 expression in cells or SAMHD1 reconstitution in knockout cells suppresses NF-kappaB activation and IFN-I induction by SeV infection or inflammatory stimuli. Mechanistically, SAMHD1 inhibits NF-kappaB activation by interacting with NF-kappaB1/2 and reducing phosphorylation of the NF-kappaB inhibitory protein IkappaBalpha. SAMHD1 also interacts with the inhibitor-kappaB kinase epsilon (IKKepsilon) and IFN regulatory factor 7 (IRF7), leading to the suppression of the IFN-I induction pathway by reducing IKKepsilon-mediated IRF7 phosphorylation. Interactions of endogenous SAMHD1 with NF-kappaB 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-kappaB 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. |
