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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 inhibits DNA virus infection.(A, B) Viral titers in L929 cells transfected with control siRNA SC and T3 (A), empty vector (Vec) or TRIM30α plasmid (B) for 24 h and then infected with HSV-1 (MOI 10) for 20 h. The titers of HSV-1 were determined by standard plaque assay. (C) Viral titers in wild type and Trim30α-/- mice intraperitoneally injected with HSV-1 (1×107 plaque-forming units (PFU)). HSV-1 titers were measured 20 h later by plaque assay of peritoneal wash fluid. (D) Real-time PCR of HSV-1 genomic DNA in the brain, lung and liver from wild type and Trim30α-/- mice infected with HSV-1 (2×107 PFU) (i.v.) for 2 days. The data are representative of three independent experiments and are presented as mean ± SEM. *p < 0.05, ***p < 0.001.
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ppat.1005012.g003: TRIM30α deficiency inhibits DNA virus infection.(A, B) Viral titers in L929 cells transfected with control siRNA SC and T3 (A), empty vector (Vec) or TRIM30α plasmid (B) for 24 h and then infected with HSV-1 (MOI 10) for 20 h. The titers of HSV-1 were determined by standard plaque assay. (C) Viral titers in wild type and Trim30α-/- mice intraperitoneally injected with HSV-1 (1×107 plaque-forming units (PFU)). HSV-1 titers were measured 20 h later by plaque assay of peritoneal wash fluid. (D) Real-time PCR of HSV-1 genomic DNA in the brain, lung and liver from wild type and Trim30α-/- mice infected with HSV-1 (2×107 PFU) (i.v.) for 2 days. The data are representative of three independent experiments and are presented as mean ± SEM. *p < 0.05, ***p < 0.001.

Mentions: To evaluate the function of TRIM30α in host antiviral responses in vitro, we knocked down the expression of TRIM30α in mouse fibroblast L929 cells and then infected these cells with the DNA virus HSV-1. As expected, TRIM30α knockdown suppressed HSV-1 infection (Fig 3A). In contrast, overexpression of TRIM30α markedly facilitated HSV-1 replication (Fig 3B). These data suggest that TRIM30α is an important negative regulator in anti-viral defense. To further identify the role of TRIM30α in vivo host defense, wild type and Trim30α-deficient mice were challenged by intraperitoneal (i.p.) injection with HSV-1, and virus titers were examined 20 h later. Significantly more HSV-1 replication was detected in wild type mice (Fig 3C).


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 inhibits DNA virus infection.(A, B) Viral titers in L929 cells transfected with control siRNA SC and T3 (A), empty vector (Vec) or TRIM30α plasmid (B) for 24 h and then infected with HSV-1 (MOI 10) for 20 h. The titers of HSV-1 were determined by standard plaque assay. (C) Viral titers in wild type and Trim30α-/- mice intraperitoneally injected with HSV-1 (1×107 plaque-forming units (PFU)). HSV-1 titers were measured 20 h later by plaque assay of peritoneal wash fluid. (D) Real-time PCR of HSV-1 genomic DNA in the brain, lung and liver from wild type and Trim30α-/- mice infected with HSV-1 (2×107 PFU) (i.v.) for 2 days. The data are representative of three independent experiments and are presented as mean ± SEM. *p < 0.05, ***p < 0.001.
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ppat.1005012.g003: TRIM30α deficiency inhibits DNA virus infection.(A, B) Viral titers in L929 cells transfected with control siRNA SC and T3 (A), empty vector (Vec) or TRIM30α plasmid (B) for 24 h and then infected with HSV-1 (MOI 10) for 20 h. The titers of HSV-1 were determined by standard plaque assay. (C) Viral titers in wild type and Trim30α-/- mice intraperitoneally injected with HSV-1 (1×107 plaque-forming units (PFU)). HSV-1 titers were measured 20 h later by plaque assay of peritoneal wash fluid. (D) Real-time PCR of HSV-1 genomic DNA in the brain, lung and liver from wild type and Trim30α-/- mice infected with HSV-1 (2×107 PFU) (i.v.) for 2 days. The data are representative of three independent experiments and are presented as mean ± SEM. *p < 0.05, ***p < 0.001.
Mentions: To evaluate the function of TRIM30α in host antiviral responses in vitro, we knocked down the expression of TRIM30α in mouse fibroblast L929 cells and then infected these cells with the DNA virus HSV-1. As expected, TRIM30α knockdown suppressed HSV-1 infection (Fig 3A). In contrast, overexpression of TRIM30α markedly facilitated HSV-1 replication (Fig 3B). These data suggest that TRIM30α is an important negative regulator in anti-viral defense. To further identify the role of TRIM30α in vivo host defense, wild type and Trim30α-deficient mice were challenged by intraperitoneal (i.p.) injection with HSV-1, and virus titers were examined 20 h later. Significantly more HSV-1 replication was detected in wild type mice (Fig 3C).

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