STING governs RCC growth through mitochondrial regulation of VDAC2
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ABSTRACT:
PROVIDER: PRJNA788511 | ENA |
REPOSITORIES: ENA
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Project description:STING is an innate immune sensor for immune surveillance of viral or bacterial infection and maintenance of an immune-friendly microenvironment to unfavored tumorigenesis. Whether and how STING exerts any innate immunity independent function remains elusive. Here, we report that STING expression is increased in RCC patients and STING governs RCC growth through non-canonical innate immune signaling by maintaining mitochondrial ROS and calcium homeostasis. Mechanistically, we identify mitochondrial calcium transporter VDAC2 as a new STING binding partner and downstream effector, through suppression of which STING controls proper mitochondrial ROS/calcium levels. We also find palmitoylation of STING-C88/C91 residues is critical to mediate STING interaction with VDAC2 and inhibiting STING palmitoyl-transferases ZDHHCs by 2-BP significantly impedes RCC cell growth. Together, our studies reveal an innate immunity-independent function of STING in regulating RCC mitochondrial function and growth. We hope our study provides a rationale to apply palmitoylation inhibitors to treating RCC.
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Project description:Fibrosis of the kidney is the final common pathway leading to end stage renal failure. By analyzing kidneys of patients and animal models with fibrosis we observed a significant mitochondrial defect, including the loss of the mitochondrial transcription factor A (TFAM) in kidney tubule cells. Here, we generated mice with tubule-specific deletion of TFAM (Ksp-Cre/Tfam flox/flox). While these mice developed severe mitochondrial loss and energetic deficit (ATP level decline) by 6 weeks of age, kidney fibrosis, immune cell infiltration and progressive azotemia causing death was only observed around 12 weeks of age. Mechanistic studies demonstrated that in the TFAM KO mice aberrant packaging of the mitochondrial DNA (mtDNA) resulted in escape of the mtDNA into the cytosol of the renal cells, activation of the cytosolic cGAS-STING (Stimulator of interferon genes) DNA sensing pathway, and thus cytokine expression and immune cell recruitment. Genetic deletion or pharmacological inhibition of STING ameliorated kidney fibrosis in mouse models of chronic kidney disease, demonstrating that in addition to its essential role in metabolism TFAM sequesters mtDNA to prevent the activation of innate immune pathways and fibrosis.
2019-08-29 | GSE134950 | GEO
Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from wild type murine embryonic fibroblasts (WT MEFs), STING deficient MEFs (SKO), Trex1 deficient MEFs (TKO), and both STING and Trex1 deficient MEFs (STKO) treated with DMBA and examined cytokine production by these cells.
2014-05-31 | E-GEOD-57603 | biostudies-arrayexpress
Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from DMBA or acetone treated wild type (WT) or STING deficient (SKO) mouse skin or skin tumor was examined for gene expression.
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