Dataset Information

BCAT1 binds the RNA-binding protein ZNF423 to activate autophagy via the IRE1-XBP-1-RIDD axis in hypoxic PASMCs.

ABSTRACT: Abnormal functional changes in pulmonary artery smooth muscle cells are the main causes of many lung diseases. Among, autophagy plays a crucial role. However, the specific molecular regulatory mechanism of autophagy in PASMCs remains unclear. Here, we first demonstrate that BCAT1 played a key role in the autophagy of hypoxic PASMCs and hypoxic model rats. BCAT1-induced activation and accumulation of the autophagy signaling proteins BECN1 and Atg5 by the endoplasmic reticulum (ER) stress pathway. Interestingly, we discovered that BCAT1 bound IRE1 on the ER to activate expression of its downstream pathway XBP-1-RIDD axis to activate autophagy. More importantly, we identified an RNA-binding protein, zinc finger protein 423, which promoted autophagy by binding adenylate/uridylate (AU)-rich elements in the BCAT1 mRNA 3'-untranslated region. Overall, our results identify BCAT1 as a potential therapeutic target for the clinical treatment of lung diseases and reveal a novel posttranscriptional regulatory mechanism and signaling pathway in hypoxia-induced PASMC autophagy.

SUBMITTER: Xin W

PROVIDER: S-EPMC7494854 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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BCAT1 binds the RNA-binding protein ZNF423 to activate autophagy via the IRE1-XBP-1-RIDD axis in hypoxic PASMCs.

Xin Wei W Zhang Min M Yu Yang Y Li Songlin S Ma Cui C Zhang Junting J Jiang Yuan Y Li Yiying Y Zheng Xiaodong X Zhang Lixin L Zhao Xijuan X Pei Xuzhong X Zhu Daling D

Cell death & disease 20200916 9

Abnormal functional changes in pulmonary artery smooth muscle cells are the main causes of many lung diseases. Among, autophagy plays a crucial role. However, the specific molecular regulatory mechanism of autophagy in PASMCs remains unclear. Here, we first demonstrate that BCAT1 played a key role in the autophagy of hypoxic PASMCs and hypoxic model rats. BCAT1-induced activation and accumulation of the autophagy signaling proteins BECN1 and Atg5 by the endoplasmic reticulum (ER) stress pathway. ...[more]

PMID: 32938905

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Project description:BackgroundYaks are animals that have lived in plateau environments for generations. Yaks can adapt to the hypoxic plateau environment and also pass this adaptability on to the next generation. The lungs are the most important respiratory organs for mammals to adapt to their environment. Pulmonary artery smooth muscle cells play an important role in vascular remodeling under hypoxia, but the genetic mechanism underpinning the yak's ability to adapt to challenging plateau conditions is still unknown.MethodsA tandem mass tag (TMT) proteomics study together with an RNA-seq transcriptome analysis were carried out on pulmonary artery smooth muscle cells (PASMCs) that had been grown for 72 hours in both normoxic (20% O2) and hypoxic (1% O2) environments. RNA and TP (total protein) were collected from the hypoxic and normoxic groups for RNA-seq transcriptome sequencing and TMT marker protein quantification, and RT-qPCR validation was performed.ResultsA total of 17,711 genes and 6,859 proteins were identified. Further, 5,969 differentially expressed genes (DEGs) and 531 differentially expressed proteins (DEPs) were identified in the comparison group, including 2,924 and 186 upregulated genes and proteins and 3,045 and 345 down-regulated genes and proteins, respectively. The transcriptomic and proteomic analyses revealed that 109 DEGs and DEPs were highly positively correlated, with 77 genes showing the same expression trend. Nine overlapping genes were identified in the HIF-1 signaling pathway, glycolysis / gluconeogenesis, central carbon metabolism in cancer, PPAR signaling pathway, AMPK signaling pathway, and cholesterol metabolism (PGAM1, PGK1, TPI1, HMOX1, IGF1R, OLR1, SCD, FABP4 and LDLR), suggesting that these differentially expressed genes and protein functional classifications are related to the hypoxia-adaptive pathways. Overall, our study offers abundant data for further analysis of the molecular mechanisms in yak PASMCs and their adaptability to different oxygen concentrations.

Dataset Information

BCAT1 binds the RNA-binding protein ZNF423 to activate autophagy via the IRE1-XBP-1-RIDD axis in hypoxic PASMCs.

Publications

BCAT1 binds the RNA-binding protein ZNF423 to activate autophagy via the IRE1-XBP-1-RIDD axis in hypoxic PASMCs.

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