title: NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses.
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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
authors.affiliation: Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.|Host-Pathogen-Interactions, Paul-Ehrlich-Institut, German Center for Infection Research (DZIF), 63225 Langen, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: König
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Oral Biology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Deng
authors.affiliation: Host-Pathogen-Interactions, Paul-Ehrlich-Institut, German Center for Infection Research (DZIF), 63225 Langen, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Riess
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jinyao
authors.initials: J
authors.lastname: Mo
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Petrucelli
authors.affiliation: Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Sunnie M
authors.initials: SM
authors.lastname: Yoh
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Brice
authors.initials: B
authors.lastname: Barefoot
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Samo
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Sempowski
authors.affiliation: Research Center for Genetic Medicine, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Research Center for Genetic Medicine, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.|Departments of Integrative Systems Biology, Biochemistry and Molecular Biology, George Washington University School of Medicine and Health Sciences, Washington DC 20037, USA.
authors.forename: Anamaris M
authors.initials: AM
authors.lastname: Colberg-Poley
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Feng
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wen
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Li-Chung
authors.initials: LC
authors.lastname: Tsao
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Duncan
authors.affiliation: Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Chanda
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Departments of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D004266:DNA Virus Infections / Q000276:immunology / Q000821:virology*; D004267:DNA Viruses / Q000502:physiology*; D015536:Down-Regulation; D005260:Female; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication; D000099197:STING Protein
chemical_list: D016899:Interferon-beta; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017346:Protein Serine-Threonine Kinases; C555655:NLRX1 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C498588:Tbk1 protein, mouse