ATF3 -activated accelerating effect of LINC00941/lncIAPF on fibroblast-to-myofibroblast differentiation by blocking autophagy depending on ELAVL1/HuR in pulmonary fibrosis
Apr 15, 2022Autophagy
LINC00941/lncIAPF speeds up fibroblast change into scar cells by blocking cell cleanup with help from ATF3 and ELAVL1/HuR in lung fibrosis
Blocking the processes of and myofibroblast proliferation is critical in managing (IPF).
Highly upregulated factors may accelerate pulmonary fibrosis by promoting fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration.
Histone 3 lysine 27 acetylation (H3K27ac) is associated with increased transcription factor ATF3 binding, enhancing transcription in certain chromosome regions.
An RNA-protein complex formed with ELAVL1/HuR is indicated to exert pro-fibrotic functions.
The ELAVL1 axis may inhibit autophagosome fusion with lysosomes, impacting autophagic processes.
The stability of target genes related to is potentially controlled by the ELAVL1 complex, affecting their expression.
Therapeutic effects have been confirmed in both a mouse model and patients with IPF.
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(IPF) is characterized by lung scarring and has no effective treatment. and myofibroblast proliferation and migration are major clinical manifestations of this disease; hence, blocking these processes is a practical treatment strategy. Here, highly upregulatedwas found to accelerate pulmonary fibrosis by promoting fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration. Assay for transposase-accessible chromatin using sequencing and chromatin immunoprecipitation experiments elucidated that histone 3 lysine 27 acetylation (H3K27ac) activated the chromosome region opening in thepromoter. As a consequence, the transcription factor ATF3 (activating transcription factor 3) bound to this region, andtranscription was enhanced. RNA affinity isolation, RNA immunoprecipitation (RIP), RNase-RIP, half-life analysis, and ubiquitination experiments unveiled thatformed a RNA-protein complex with ELAVL1/HuR (ELAV like RNA binding protein 1) to exert its pro-fibrotic function. Dual-fluorescence mRFP-GFP-MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) adenovirus monitoring technology, human RTprofiler PCR array, and autophagic flux revealed that the-ELAVL1 axis inhibited autophagosome fusion with a lysosome. ELAVL1 RIP-seq, RIP-PCR, mRNA stability, and rescue experiments showed that the-ELAVL1 complex inhibited autophagy by controlling the stability of the target genes(enhancer of zeste 2 polycomb repressive complex 2 subunit),(signal transducer and activators of transcription 1) and(forkhead box K1). Finally, the therapeutic effect ofwas confirmed in a mouse model and patients with IPF. This work provides a therapeutic target and a new effective therapeutic strategy related to autophagy for IPF.ACTA2/a-SMA: actin alpha 2, smooth muscle; ATF3: activating transcription factor 3; ATG: autophagy related; Baf-A1: bafilomycin A; BLM: bleomycin; CDKN: cyclin dependent kinase inhibitor; CLN3: CLN3 lysosomal/endosomal transmembrane protein, battenin; COL1A: collagen type I alpha; COL3A: collagen type III alpha; CXCR4: C-X-C motif chemokine receptor 4; DRAM2: DNA damage regulated autophagy modulator 2; ELAVL1/HuR: ELAV like RNA binding protein 1; EZH2: enhancer of zeste 2 polycomb repressive complex 2 subunit; FADD: Fas associated via death domain; FAP/FAPα: fibroblast activation protein alpha; FOXK1: forkhead box K1; FVC: forced vital capacity; GABARAP: GABA type A receptor-associated protein; GABARAPL2: GABA type A receptor associated protein like 2; IGF1: insulin like growth factor 1; IPF: idiopathic pulmonary fibrosis; LAMP: lysosomal associated membrane protein; lncRNA: long noncoding RNA; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPC1: NPC intracellular cholesterol transporter 1; RGS: regulator of G protein signaling; RPLP0: ribosomal protein lateral stalk subunit P0; ROC: receiver operating characteristic; S100A4: S100 calcium binding protein A4; SQSTM1/p62: sequestosome 1; STAT1: signal transducers and activators of transcription 1; TGFB1/TGF-β1: transforming growth factor beta 1; TNF: tumor necrosis factor; UIP: usual interstitial pneumonia; ULK1: unc-51 like autophagy activating kinase 1; VIM: vimentin. LINC00941/lncIAPF LINC00941LINC00941LINC00941LINC00941LINC00941EZH2STAT1FOXK1LINC00941 2Abbreviations: 1
Key numbers
FVC improved in si-group
FVC Improvement
Forced vital capacity (FVC) was assessed in treated mice.
Sensitivity 87.5%, Specificity 75.0%
Sensitivity and Specificity
ROC analysis showed these values for LINC00941/lncIAPF in patients.
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