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Cell Host Microbe. 2016 Apr 13;19(4):515-528. doi: 10.1016/j.chom.2016.03.001.

NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses.

Author information

1
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
2
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
3
Host-Pathogen-Interactions, Paul-Ehrlich-Institut, German Center for Infection Research (DZIF), 63225 Langen, Germany.
4
Department of Oral Biology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5
Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
6
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
7
Research Center for Genetic Medicine, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
8
Departments of Integrative Systems Biology, Biochemistry and Molecular Biology, George Washington University School of Medicine and Health Sciences, Washington DC 20037, USA.
9
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
10
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
11
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
12
Departments of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
#
Contributed equally

Abstract

Understanding the negative regulators of antiviral immune responses will be critical for advancing immune-modulated antiviral strategies. NLRX1, an NLR protein that negatively regulates innate immunity, was previously identified in an unbiased siRNA screen as required for HIV infection. We find that NLRX1 depletion results in impaired nuclear import of HIV-1 DNA in human monocytic cells. Additionally, NLRX1 was observed to reduce type-I interferon (IFN-I) and cytokines in response to HIV-1 reverse-transcribed DNA. NLRX1 sequesters the DNA-sensing adaptor STING from interaction with TANK-binding kinase 1 (TBK1), which is a requisite for IFN-1 induction in response to DNA. NLRX1-deficient cells generate an amplified STING-dependent host response to cytosolic DNA, c-di-GMP, cGAMP, HIV-1, and DNA viruses. Accordingly, Nlrx1(-/-) mice infected with DNA viruses exhibit enhanced innate immunity and reduced viral load. Thus, NLRX1 is a negative regulator of the host innate immune response to HIV-1 and DNA viruses.

PMID:
27078069
PMCID:
PMC4833116
DOI:
10.1016/j.chom.2016.03.001
[Indexed for MEDLINE]
Free PMC Article

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