DEK deficiency suppresses mitophagy to protect against house dust mite-induced asthma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1018871 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26111223_1.fastq.gz | Fastqsanger.gz | |||
| SRR26111223_2.fastq.gz | Fastqsanger.gz | |||
| SRR26111224_1.fastq.gz | Fastqsanger.gz | |||
| SRR26111224_2.fastq.gz | Fastqsanger.gz |
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Project description:This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PTEN-induced putative kinase 1 (PINK1)-Parkin mediated mitophagy, NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, and apoptosis. We found that recombinant DEK protein (rmDEK) promoted eosinophils recruitment, mitochondrial fragmentation, and outer membrane 20 (TOM20) and LC3 co-localization representing mitophagosomes in bronchoalveolar lavage fluid (BALF) in house dust mite (HDM) induced-asthma. rmDEK also reduced co-localization of mitochondrial fusion protein mitofusin1 (MFN1) and mitochondria, and the protein level of manganese superoxide dismutase (MnSOD), enhanced microtubule-associated protein1 light chain 3 (LC3) and voltage-dependent anion channels (VDAC) co-localization which also represent the mitophagosomes in airway epithelial cells, furthermore, increased dynamin-related protein 1 (DRP1) expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. In the DEK knockout mice, HDM induced asthmatic airway inflammation, MnSOD, PINK1-Parkin protein level, Parkin mediated mitophagy characterized by LC3 and Parkin co-localization in the airways, ROS generation, NLRP3 inflammation and apoptosis were fully reversed. Similar effects of rmDEK were also observed in the BEAS-2B cells, which were rescued by the autophagy inhibitor 3-MA. Moreover, DEK silencing diminished the Parkin, LC3, DRP1 translocation to mitochondria; as well as mitochondrial ROS; TOM20 and mitochondrial DNA mediated mitochondrial oxidative damage. ChIP-sequence analysis showed that DEK was enriched on the AAA domain-containing protein 3A (ATAD3A) promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models. Furthermore, ATAD3A interacted with DRP1, and knockdown of ATAD3A could down-regulate DRP1 and mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.
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Project description:DEK protein is highly expressed in asthma. However, the mechanism of DEK on mitophagy in asthma has not been fully understood. This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. PINK1-Parkin mitophagy, NLRP3 inflammasome, and apoptosis were examined after gene silencing or treatment with specific inhibitors (MitoTEMPO, MCC950, and Ac-DEVD-CHO) in house dust mite (HDM) or recombinant DEK (rmDEK)-induced WT and DEK-/- asthmatic mice and BEAS-2B cells. The regulatory role of DEK on ATAD3A was detected using ChIP-sequence and co-immunoprecipitation. rmDEK promoted eosinophil recruitment, and co-localization of TOM20 and LC3B, MFN1 and mitochondria, LC3B and VDAC, and ROS generation, reduced protein level of MnSOD in HDM induced-asthmatic mice. Moreover, rmDEK also increased DRP1 expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. These effects were partially reversed in DEK-/- mice. In BEAS-2B cells, siDEK diminished the Parkin, LC3B, and DRP1 translocation to mitochondria, mtROS, TOM20, and mtDNA. ChIP-sequence analysis showed that DEK was enriched on the ATAD3A promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models and interacted with DRP1, and siATAD3A could down-regulate DRP1 and mtDNA-mediated mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.
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