DCAF1 regulates Treg senescence via the ROS axis during immunological aging
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ABSTRACT:
PROVIDER: PRJNA540226 | ENA |
REPOSITORIES: ENA
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Project description:As a hallmark of immunological aging, low-grade, chronic inflammation with accumulation of effector memory T cells contributes to increased susceptibility to many aging-related diseases. While the proinflammatory state of aged T cells indicates a dysregulation of immune homeostasis, whether and how aging drives regulatory T cell (Treg) aging and alters Treg function are not fully understood owing to a lack of specific aging markers. Here, by a combination of cellular, molecular, and bioinformatic approaches, we discovered that Tregs senesce more severely than conventional T (Tconv) cells during aging. We found that Tregs from aged mice were less efficient than young Tregs in suppressing Tconv cell function in an inflammatory bowel disease model and in preventing Tconv cell aging in an irradiation-induced aging model. Furthermore, we revealed that DDB1- and CUL4-associated factor 1 (DCAF1) was downregulated in aged Tregs and was critical to restrain Treg aging via reactive oxygen species (ROS) regulated by glutathione-S-transferase P (GSTP1). Importantly, interfering with GSTP1 and ROS pathways reinvigorated the proliferation and function of aged Tregs. Therefore, our studies uncover an important role of the DCAF1/GSTP1/ROS axis in Treg senescence, which leads to uncontrolled inflammation and immunological aging.
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Project description:Total RNA of regulatory T (Treg) cells and conventional CD4 T (Tconv) cells from young WT (2 months), aged WT (>18 months) and young Dcaf1-deficient mice was extracted and RNA-seq libraries were generated. Reads (32-45 Million reads per sample) were analyzed with Salmon software to align and quantify the transcript expression. R packages in Bioconductor, tximport and tximportData were used to aggregate transcript-level quantifications to the gene level, with the R package biomaRt for gene and transcripts mapping. The option "lengthScaledTPM" for countsFromAbundance in tximport was used to obtain the estimated counts at the gene level using abundance estimates scaled based on the average transcript length over samples and the library size. The option "lengthScaledTPM" for countsFromAbundance in tximport was used to obtain the estimated counts at the gene level using abundance estimates scaled based on the average transcript length over samples and the library size. For the differential expression (DE) analysis of RNA-seq data, gene-level count matrix was passed into by DESeq2 package as input directly from the tximport package. The normalized gene expression data was retrieved from DESeq2 analysis after regulated log (rlog) transformation (‘rlog’ in DESeq2). The z-score at gene-level average of normalized expression matrix was used to generate heatmap in Gene-E from Broad Institute (www.broadinstitute.org/ /GENE-E/). Gene Set Enrichment Analysis was performed using the Java application available from Broad Institute (www.broadinstitute.org/gsea/). Gene set databases including Hallmarks (h.all.v6.1.symbols.gmt) and KEGG (c2.cp.kegg.v6.1.symbols.gmt) from the Molecular Signatures Database (MSigDB) were used in the analysis. The aging-program gene set was from DEMAGALHAES_AGING_UP in MSigDB. One thousand gene set permutations were performed. FDR<0.05 was used for enriched terms, as is recommended when performing permutations by gene set.
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Project description:Kidney is a vital organ responsible for homeostasis in the body. To retard kidney aging is of great importance for maintaining body health. Whereas the therapeutic strategies targeting against kidney aging are not elucidated. Recent studies show mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, however, the underlying mechanisms of mitochondrial dysfunction in kidney aging have not been demonstrated. Herein, we found calcium overload, and the mitochondrial calcium uniporter (MCU) was induced in renal tubular cells and aged kidney. To activate MCU not only triggered mitochondrial calcium overload, but also induced reactive oxygen species (ROS) production and cellular senescence and age-related kidney fibrosis. Inversely, to block MCU or chelate calcium diminished ROS generation, restored mitochondrial homeostasis, and retarded cell senescence and protected against kidney aging. These results demonstrate MCU plays a key role in promote renal tubular cell senescence, which provides a new insight on the therapeutic strategy for fighting against kidney aging.
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