학술논문
The dNTPase activity of SAMHD1 is important for its suppression of innate immune responses in differentiated monocytic cells.
Document Type
Academic Journal
Author
Qin Z; Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210; Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.; Bonifati S; Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210.; St Gelais C; Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210.; Li TW; Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210.; Kim SH; Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210.; Antonucci JM; Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210.; Mahboubi B; Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322.; Yount JS; Department of Microbial Infection and Immunity, Infectious Diseases Institute, The Ohio State University, Columbus, Ohio 43210.; Xiong Y; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520.; Kim B; Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322.; Wu L; Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210; Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242; Department of Microbial Infection and Immunity, Infectious Diseases Institute, The Ohio State University, Columbus, Ohio 43210. Electronic address: li-wu@uiowa.edu.
Source
Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
Subject
Language
English
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 ( TNF- α) and interleukin-6 ( IL-6 ) mRNAs, as well as IFN- α, IFN- β, and TNF- 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 TNF- α or IFN- 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.
(© 2020 Qin et al.)
(© 2020 Qin et al.)