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TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING.

Wang Y, Lian Q, Yang B, Yan S, Zhou H, He L, Lin G, Lian Z, Jiang Z, Sun B - PLoS Pathog. (2015)

Bottom Line: Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host.Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response.Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Sciences, University of Science and Technology of China, Hefei, China.

ABSTRACT
Uncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30α (TRIM30α) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30α augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.

No MeSH data available.


Related in: MedlinePlus

TRIM30α deficiency protects the mice from DNA virus infection.(A, B) ELISA of IFN-β and IL-6 in wild-type and Trim30α-/- CD11c+ splenocytes stimulated for 24 h with ISD (1 μg/ml), HSV-1 (MOI 10) or poly(I:C) (5 μg/ml). (C, D) Real-time PCR of IFN-β and TNF-α in the lung and liver from wild type and Trim30α-/- mice infected with HSV-1 (2×107 PFU) (i.v.) for the indicated times. (E) ELISA of IFN-β and IL-6 in serum of wild type and Trim30α-/- mice 6 h after intravenous infection with HSV-1 (1.2×107 PFU) (n = 5). (F) Survival of age- and sex-matched wild-type and Trim30α-/- mice (n = 5 per group) infected with HSV-1 (2×107 PFU) (i.v.) and monitored daily for 15 d. The data are representative of three independent experiments and are presented as mean ± SEM. *p < 0.05, **p < 0.01 and ***p < 0.001.
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ppat.1005012.g004: TRIM30α deficiency protects the mice from DNA virus infection.(A, B) ELISA of IFN-β and IL-6 in wild-type and Trim30α-/- CD11c+ splenocytes stimulated for 24 h with ISD (1 μg/ml), HSV-1 (MOI 10) or poly(I:C) (5 μg/ml). (C, D) Real-time PCR of IFN-β and TNF-α in the lung and liver from wild type and Trim30α-/- mice infected with HSV-1 (2×107 PFU) (i.v.) for the indicated times. (E) ELISA of IFN-β and IL-6 in serum of wild type and Trim30α-/- mice 6 h after intravenous infection with HSV-1 (1.2×107 PFU) (n = 5). (F) Survival of age- and sex-matched wild-type and Trim30α-/- mice (n = 5 per group) infected with HSV-1 (2×107 PFU) (i.v.) and monitored daily for 15 d. The data are representative of three independent experiments and are presented as mean ± SEM. *p < 0.05, **p < 0.01 and ***p < 0.001.

Mentions: To investigate the role of TRIM30α in host antiviral innate response, we isolated CD11c+ splenocytes from wild-type and Trim30α-deficient mice and treated these cells for 16 h with ISD, HSV-1 or poly(I:C). The Trim30α-deficient CD11c+ splenocytes produced high levels of IFN-β and IL-6 upon stimulation with ISD and HSV-1. However, TRIM30α deficiency had little effect on poly(I:C)-triggered response (Fig 4A and 4B). Besides DCs, macrophages are also involved in immune response triggered by intracellular DNA or DNA virus. We then obtained peritoneal macrophages (PM) from wild type and Trim30α-/- mice and then the above PM were stimulated with ISD or infected with HSV-1. The real-time PCR analysis demonstrated that Trim30α-/- PM produced more type I IFN and ISGs, suggesting that the negative role of TRIM30α in regulating DNA-sensing signaling pathway was not restricted in DCs (S4A and S4B Fig).


TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING.

Wang Y, Lian Q, Yang B, Yan S, Zhou H, He L, Lin G, Lian Z, Jiang Z, Sun B - PLoS Pathog. (2015)

TRIM30α deficiency protects the mice from DNA virus infection.(A, B) ELISA of IFN-β and IL-6 in wild-type and Trim30α-/- CD11c+ splenocytes stimulated for 24 h with ISD (1 μg/ml), HSV-1 (MOI 10) or poly(I:C) (5 μg/ml). (C, D) Real-time PCR of IFN-β and TNF-α in the lung and liver from wild type and Trim30α-/- mice infected with HSV-1 (2×107 PFU) (i.v.) for the indicated times. (E) ELISA of IFN-β and IL-6 in serum of wild type and Trim30α-/- mice 6 h after intravenous infection with HSV-1 (1.2×107 PFU) (n = 5). (F) Survival of age- and sex-matched wild-type and Trim30α-/- mice (n = 5 per group) infected with HSV-1 (2×107 PFU) (i.v.) and monitored daily for 15 d. The data are representative of three independent experiments and are presented as mean ± SEM. *p < 0.05, **p < 0.01 and ***p < 0.001.
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ppat.1005012.g004: TRIM30α deficiency protects the mice from DNA virus infection.(A, B) ELISA of IFN-β and IL-6 in wild-type and Trim30α-/- CD11c+ splenocytes stimulated for 24 h with ISD (1 μg/ml), HSV-1 (MOI 10) or poly(I:C) (5 μg/ml). (C, D) Real-time PCR of IFN-β and TNF-α in the lung and liver from wild type and Trim30α-/- mice infected with HSV-1 (2×107 PFU) (i.v.) for the indicated times. (E) ELISA of IFN-β and IL-6 in serum of wild type and Trim30α-/- mice 6 h after intravenous infection with HSV-1 (1.2×107 PFU) (n = 5). (F) Survival of age- and sex-matched wild-type and Trim30α-/- mice (n = 5 per group) infected with HSV-1 (2×107 PFU) (i.v.) and monitored daily for 15 d. The data are representative of three independent experiments and are presented as mean ± SEM. *p < 0.05, **p < 0.01 and ***p < 0.001.
Mentions: To investigate the role of TRIM30α in host antiviral innate response, we isolated CD11c+ splenocytes from wild-type and Trim30α-deficient mice and treated these cells for 16 h with ISD, HSV-1 or poly(I:C). The Trim30α-deficient CD11c+ splenocytes produced high levels of IFN-β and IL-6 upon stimulation with ISD and HSV-1. However, TRIM30α deficiency had little effect on poly(I:C)-triggered response (Fig 4A and 4B). Besides DCs, macrophages are also involved in immune response triggered by intracellular DNA or DNA virus. We then obtained peritoneal macrophages (PM) from wild type and Trim30α-/- mice and then the above PM were stimulated with ISD or infected with HSV-1. The real-time PCR analysis demonstrated that Trim30α-/- PM produced more type I IFN and ISGs, suggesting that the negative role of TRIM30α in regulating DNA-sensing signaling pathway was not restricted in DCs (S4A and S4B Fig).

Bottom Line: Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host.Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response.Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Sciences, University of Science and Technology of China, Hefei, China.

ABSTRACT
Uncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30α (TRIM30α) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30α augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.

No MeSH data available.


Related in: MedlinePlus