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ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE251885 | GEO | 2023/12/31

REPOSITORIES: GEO

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ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis [RNA-seq]

Project description:Abstract：Our previous study found that 1-nitropyrene (1-NP) exposure evoked pulmonary fibrosis in mice. However, the exact mechanism remained elusive. We found that 1-NP induced telomere damage and cellular senescence in mice lungs and MLE-12 cells. Further research showed that 1-NP downregulated telomere repeat binding factor 2 (TRF2), and upregulated FBXW7. Mechanistically, 1-NP-caused TRF2 ubiquitination and proteasomal degradation depended on E3 ubiquitin ligase activity of FBXW7. Moreover, 1-NP upregulated FBXW7 m6A modification via an ALKBH5-YTHDF1-dependent manner. Further analysis found 1-NP promoted ALKBH5 SUMOylation and subsequent proteasomal degradation. Additionally, 1-NP evoked mitochondrial reactive oxygen species (mtROS) overproduction. Mito-TEMPO, a mitochondrial-targeted antioxidant, mitigated 1-NP-caused mtROS overproduction, ALKBH5 SUMOylation, FBXW7 m6A modification, TRF2 degradation and cellular senescence. Taken together, mtROS-initiated ALKBH5 SUMOylation and subsequent FBXW7 m6A modification is indispensable in TRF2 degradation and cellular senescence in pulmonary epithelial cells during 1-NP-induced pulmonary fibrosis. Our study provides target intervention measures towards 1-NP-evoked pulmonary fibrosis.

2023-12-31 | GSE251884 | GEO

ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis [Ribo-seq]

2023-12-31 | GSE251659 | GEO

ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis

Project description:ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis

| PRJNA1055612 | ENA

ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis [RNA-seq]

Project description:ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis [RNA-seq]

| PRJNA1055667 | ENA

ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis [Ribo-seq]

Project description:ALKBH5 SUMOylation-mediated FBXW7 m6A modification regulates epithelial cells senescence during 1-nitropyrene-induced pulmonary fibrosis [Ribo-seq]

| PRJNA1055023 | ENA

Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response.

Project description:Faithful genome integrity maintenance plays an essential role in cell survival. Here, we identify the RNA demethylase ALKBH5 as a key regulator that protects cells from DNA damage and apoptosis during reactive oxygen species (ROS)-induced stress. We find that ROS significantly induces global mRNA N6-methyladenosine (m6A) levels by modulating ALKBH5 post-translational modifications (PTMs), leading to the rapid and efficient induction of thousands of genes involved in a variety of biological processes including DNA damage repair. Mechanistically, ROS promotes ALKBH5 SUMOylation through activating ERK/JNK signaling, leading to inhibition of ALKBH5 m6A demethylase activity by blocking substrate accessibility. Moreover, ERK/JNK/ALKBH5-PTMs/m6A axis is activated by ROS in hematopoietic stem/progenitor cells (HSPCs) in vivo in mice, suggesting a physiological role of this molecular pathway in the maintenance of genome stability in HSPCs. Together, our study uncovers a molecular mechanism involving ALKBH5 PTMs and increased mRNA m6A levels that protect genomic integrity of cells in response to ROS.

| S-EPMC8191756 | biostudies-literature

ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Project description:Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

| S-EPMC10914760 | biostudies-literature

Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification.

Project description:BackgroundGastric cancer (GC) is one of the most pernicious tumors that seriously harm human healthcare. GC metastasis is one of the prime cause of failed cancer treatment, but correlation between N6-methyladenosine (m6A) and GC metastasis was less reported.MethodsMethylated RNA immunoprecipitation sequencing (MeRIP-seq) of GC tissues was conducted. Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) were taken to determine the expression of ALKBH5 in GC tissues and cell lines. RNA-seq together with MeRIP-qRT-PCR was used to screen the target gene of ALKBH5. RNA pulldown, mass spectrometry and RNA immunoprecipitation (RIP) were used to search the "reader" protein of target gene. The mechanism was also validated via a tail vein injection method for lung metastasis model.ResultsDecreased expression of ALKBH5 was detected in GC samples, and it was correlated with clinical tumor distal metastasis and lymph node metastasis. ALKBH5 interference promoted metastasis of GC cells and this effect was closely related to the demethylase activity of ALKBH5. PKMYT1, as a downstream target of ALKBH5, promoted invasion and migration in GC. Caused by ALKBH5 knockdown or its demethylase activity mutation, upregulated expression of PKMYT1 indicated that ALKBH5 modulates expression of PKMYT1 in an m6A-dependent manner. IGF2BP3 helped stabilize the mRNA stability of PKMYT1 via its m6A modification site.ConclusionsThis study established an ALKBH5-PKMYT1-IGF2BP3 regulation system in metastasis, representing a new therapeutic target for GC metastasis.

| S-EPMC8812266 | biostudies-literature

YTHDC1 delays cellular senescence and pulmonary fibrosis by activating ATR in an m6A-independent manner

Project description: Not available

| S-BSST1092 | biostudies-other

YTHDC1 delays cellular senescence and pulmonary fibrosis by activating ATR in an m6A-independent manner

Project description:Accumulation of DNA damage in the lung induces cellular senescence and promotes age-related diseases such as idiopathic pulmonary fibrosis (IPF). Hence, understanding the mechanistic regulation of DNA damage repair is important for anti-aging therapies and disease control. Here, we identified an m6A-independent role of the RNA-binding protein YTHDC1 in counteracting stress-induced pulmonary senescence and fibrosis. YTHDC1 is primarily expressed in pulmonary alveolar epithelial type 2 (AECII) cells and its AECII expression is significantly decreased in AECIIs during fibrosis. Exogenous overexpression of YTHDC1 alleviates pulmonary senescence and fibrosis of its m6A-binding ability, while YTHDC1 deletion enhances disease progression in mice. Mechanistically, YTHDC1 promotes the interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair. These findings reveal an noncanonical function of YTHDC1 in delaying cellular senescence, and suggest that enhancing YTHDC1 expression in the lung could be an effective treatment strategy for pulmonary fibrosis.

| S-SCDT-10_1038-S44318-023-00003-2 | biostudies-other

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