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

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

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

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 DamaniaLi Chung Tsao, Qi Wang, Lishan Su, Joseph A. Duncan, Sumit K. Chanda, Jenny P.Y. Ting

Pathology & Microbiology

Research output: Contribution to journal › Article › peer-review

138 Scopus citations

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.

Original language	English (US)
Pages (from-to)	515-528
Number of pages	14
Journal	Cell Host and Microbe
Volume	19
Issue number	4
DOIs	https://doi.org/10.1016/j.chom.2016.03.001
State	Published - Apr 13 2016

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

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Guo, H., König, R., Deng, M., Riess, M., Mo, J., Zhang, L., Petrucelli, A., Yoh, S. M., Barefoot, B., Samo, M., Sempowski, G. D., Zhang, A., Colberg-Poley, A. M., Feng, H., Lemon, S. M., Liu, Y., Zhang, Y., Wen, H., Zhang, Z., ... Ting, J. P. Y. (2016). NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses. Cell Host and Microbe, 19(4), 515-528. https://doi.org/10.1016/j.chom.2016.03.001

Guo, H, König, R, Deng, M, Riess, M, Mo, J, Zhang, L, Petrucelli, A, Yoh, SM, Barefoot, B, Samo, M, Sempowski, GD, Zhang, A, Colberg-Poley, AM, Feng, H, Lemon, SM, Liu, Y, Zhang, Y, Wen, H, Zhang, Z, Damania, B, Tsao, LC, Wang, Q, Su, L, Duncan, JA, Chanda, SK & Ting, JPY 2016, 'NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses', Cell Host and Microbe, vol. 19, no. 4, pp. 515-528. https://doi.org/10.1016/j.chom.2016.03.001

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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.",

author = "Haitao Guo and Renate K{\"o}nig and Meng Deng and Maximilian Riess and Jinyao Mo and Lu Zhang and Alex Petrucelli and Yoh, {Sunnie M.} and Brice Barefoot and Melissa Samo and Sempowski, {Gregory D.} and Aiping Zhang and Colberg-Poley, {Anamaris M.} and Hui Feng and Lemon, {Stanley M.} and Yong Liu and Yanping Zhang and Haitao Wen and Zhigang Zhang and Blossom Damania and Tsao, {Li Chung} and Qi Wang and Lishan Su and Duncan, {Joseph A.} and Chanda, {Sumit K.} and Ting, {Jenny P.Y.}",

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doi = "10.1016/j.chom.2016.03.001",

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AU - Guo, Haitao

AU - König, Renate

AU - Deng, Meng

AU - Riess, Maximilian

AU - Mo, Jinyao

AU - Zhang, Lu

AU - Petrucelli, Alex

AU - Yoh, Sunnie M.

AU - Barefoot, Brice

AU - Samo, Melissa

AU - Sempowski, Gregory D.

AU - Zhang, Aiping

AU - Colberg-Poley, Anamaris M.

AU - Feng, Hui

AU - Lemon, Stanley M.

AU - Liu, Yong

AU - Zhang, Yanping

AU - Wen, Haitao

AU - Zhang, Zhigang

AU - Damania, Blossom

AU - Tsao, Li Chung

AU - Wang, Qi

AU - Su, Lishan

AU - Duncan, Joseph A.

AU - Chanda, Sumit K.

AU - Ting, Jenny P.Y.

PY - 2016/4/13

Y1 - 2016/4/13

N2 - 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.

AB - 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.

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

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