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J Biol Chem. 2017 Jan 6;292(1):264-277. doi: 10.1074/jbc.M116.752584. Epub 2016 Dec 1.

Interferons Induce Expression of SAMHD1 in Monocytes through Down-regulation of miR-181a and miR-30a.

Author information

1
From the Host-Pathogen Interactions Group and.
2
the Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697.
3
the Division of Medical Biotechnology, Paul-Ehrlich-Institute, 63225 Langen, Germany.
4
From the Host-Pathogen Interactions Group and renate.koenig@pei.de.
5
the Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, and.
6
the German Center for Infection Research (DZIF), 63225 Langen, Germany.

Abstract

SAMHD1 is a phosphohydrolase maintaining cellular dNTP homeostasis but also acts as a critical regulator in innate immune responses due to its antiviral activity and association with autoimmune disease, leading to aberrant activation of interferon. SAMHD1 expression is differentially regulated by interferon in certain primary cells, but the underlying mechanism is not understood. Here, we report a detailed characterization of the promotor region, the 5'- and 3'-untranslated region (UTR) of SAMHD1, and the mechanism responsible for the cell type-dependent up-regulation of SAMHD1 protein by interferon. We demonstrate that induction of SAMHD1 by type I and II interferons depends on 3'-UTR post-transcriptional regulation, whereas the promoter drives basal expression levels. We reveal novel functional target sites for the microRNAs miR-181a, miR-30a, and miR-155 in the SAMHD1 3'-UTR. Furthermore, we demonstrate that down-regulation of endogenous miR-181a and miR-30a levels inversely correlates with SAMHD1 protein up-regulation upon type I and II interferon stimulation in primary human monocytes. These miRNAs are not modulated by interferon in macrophages or dendritic cells, and consequently protein levels of SAMHD1 remain unchanged. These results suggest that SAMHD1 is a non-classical interferon-stimulated gene regulated through cell type-dependent down-regulation of miR-181a and miR-30a in innate sentinel cells.

KEYWORDS:

SAM domain and HD domain-containing protein 1 (SAMHD1); dNTPase; human immunodeficiency virus (HIV); innate immunity; innate sentinel cells; interferon; interferon stimulated gene; microRNA (miRNA); promoter; regulation of expression

PMID:
27909056
PMCID:
PMC5217685
[Available on 2018-01-06]
DOI:
10.1074/jbc.M116.752584
[Indexed for MEDLINE]
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