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: Haitao Guo, Renate König, Meng Deng, Maximilian Riess, Jinyao Mo, Lu Zhang, Alex Petrucelli, Sunnie M Yoh, Brice Barefoot, Melissa Samo, Gregory D Sempowski, Aiping Zhang, Anamaris M Colberg-Poley, Hui Feng, Stanley M Lemon, Yong Liu, Yanping Zhang, Haitao Wen, Zhigang Zhang, Blossom Damania, Li-Chung Tsao, Qi Wang, Lishan Su, Joseph A Duncan, Sumit K Chanda, Jenny P-Y Ting
• Journal: Cell host & microbe (Cell Host Microbe) Vol. 19 Issue 4 Pg. 515-528 (Apr 13 2016) ISSN: 1934-6069 [Electronic] United States
• PMID: 27078069 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Mitochondrial Proteins
• NLRX1 protein, mouse
• Sting1 protein, mouse
• Interferon-beta
• Tbk1 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• DNA Virus Infections (immunology, virology)
• DNA Viruses (physiology)
• Down-Regulation
• Female
• HIV Infections (genetics, immunology, metabolism, virology)
• HIV-1 (genetics, physiology)
• Humans
• Immunity, Innate
• Interferon-beta (genetics, immunology)
• Male
• Membrane Proteins (genetics, immunology, metabolism)
• Mice
• Mice, Knockout
• Mitochondrial Proteins (genetics, metabolism)
• Protein Binding
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Virus Replication