The dNTPase activity of SAMHD1 is important for its suppression of innate immune responses in differentiated monocytic cells

Zhihua Qin; Serena Bonifati; Corine St Gelais; Tai-Wei Li; Sun-Hee Kim; Jenna M Antonucci; Bijan Mahboubi; Jacob S Yount; Yong Xiong; Baek Kim; Li Wu

doi:10.1074/jbc.ra119.010360

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The dNTPase activity of SAMHD1 is important for its suppression of innate immune responses in differentiated monocytic cells

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The dNTPase activity of SAMHD1 is important for its suppression of innate immune responses in differentiated monocytic cells

Zhihua Qin, Serena Bonifati, Corine St Gelais, Tai-Wei Li, Sun-Hee Kim, Jenna M Antonucci, Bijan Mahboubi, Jacob S Yount, Yong Xiong, Baek Kim, …

The Journal of biological chemistry, Vol.295(6), pp.1575-1586

02/07/2020

DOI: 10.1074/jbc.ra119.010360

PMCID: PMC7008377

PMID: 31914403

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Abstract

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphohydrolase (dNTPase) with a nuclear localization signal (NLS). SAMHD1 suppresses innate immune responses to viral infection and inflammatory stimuli by inhibiting the NF-κB and type I interferon (IFN-I) pathways. However, whether the dNTPase activity and nuclear localization of SAMHD1 are required for its suppression of innate immunity remains unknown. Here, we report that the dNTPase activity, but not nuclear localization of SAMHD1, is important for its suppression of innate immune responses in differentiated monocytic cells. We generated monocytic U937 cell lines stably expressing WT SAMHD1 or mutated variants defective in dNTPase activity (HD/RN) or nuclear localization (mNLS). WT SAMHD1 in differentiated U937 cells significantly inhibited lipopolysaccharide-induced expression of tumor necrosis factor α ( α) and interleukin-6 ( ) mRNAs, as well as α, β, and α mRNA levels induced by Sendai virus infection. In contrast, the HD/RN mutant did not exhibit this inhibition in either U937 or THP-1 cells, indicating that the dNTPase activity of SAMHD1 is important for suppressing NF-κB activation. Of note, in lipopolysaccharide-treated or Sendai virus-infected U937 or THP-1 cells, the mNLS variant reduced α or β mRNA expression to a similar extent as did WT SAMHD1, suggesting that SAMHD1-mediated inhibition of innate immune responses is independent of SAMHD1's nuclear localization. Moreover, WT and mutant SAMHD1 similarly interacted with key proteins in NF-κB and IFN-I pathways in cells. This study further defines the role and mechanisms of SAMHD1 in suppressing innate immunity.

Cell Differentiation

Inflammation

type I interferon (IFN-I)

SAM domain and HD domain-containing protein 1 (SAMHD1)

viral restriction factor

NF-kappa B (NF-KB)

SAMHD1

interferon

dNTPase activity

monocytic cells

NF-kB transcription factor

innate immunity

nuclear localization

NF-κB activation

monocyte

innate immune responses

Details

Title: Subtitle: The dNTPase activity of SAMHD1 is important for its suppression of innate immune responses in differentiated monocytic cells
Creators: Zhihua Qin - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
Serena Bonifati - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210
Corine St Gelais - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210
Tai-Wei Li - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210
Sun-Hee Kim - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210
Jenna M Antonucci - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210
Bijan Mahboubi - Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322
Jacob S Yount - Department of Microbial Infection and Immunity, Infectious Diseases Institute, The Ohio State University, Columbus, Ohio 43210
Yong Xiong - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520
Baek Kim - Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322
Li Wu - Department of Microbial Infection and Immunity, Infectious Diseases Institute, The Ohio State University, Columbus, Ohio 43210
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.295(6), pp.1575-1586
DOI: 10.1074/jbc.ra119.010360
PMID: 31914403
PMCID: PMC7008377
NLM abbreviation: J Biol Chem
ISSN: 1083-351X
eISSN: 1083-351X
Publisher: United States
Grant note: R01 AI150451 / NIAID NIH HHS R01 AI141495 / NIAID NIH HHS R01 AI150343 / NIAID NIH HHS
Language: English
Date published: 02/07/2020
Academic Unit: Microbiology and Immunology
Record Identifier: 9984001229402771

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