Sodium arsenite-induced cytotoxicity is regulated by BNIP3L/Nix-mediated endoplasmic reticulum stress responses and CCPG1-mediated endoplasmic reticulum-phagy

We elucidated the BNIP3L/Nix and SQSTM1/p62 molecular mechanisms in sodium arsenite (NaAR)-induced cytotoxicity. Considerable changes in the morphology and adhesion of H460 cells were observed in response to varying NaAR concentrations. NaAR exposure induced DNA damage-mediated apoptosis and Nix acc...

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Published in:Environmental toxicology and pharmacology 2023-04, Vol.99, p.104111-104111, Article 104111
Main Authors: Kim, Sang-Hun, Oh, Seon-Hee
Format: Article
Language:English
Subjects:
Apoptosis Regulatory Proteins - metabolism
Autophagy - genetics
Calnexin - metabolism
CCPG1
Cell Cycle Proteins - metabolism
Endoplasmic Reticulum - genetics
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum Stress
ER stress
ER-phagy
Lung toxicity
Membrane Proteins - metabolism
Mitochondrial Proteins - metabolism
Nix
Sodium arsenite
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Summary:We elucidated the BNIP3L/Nix and SQSTM1/p62 molecular mechanisms in sodium arsenite (NaAR)-induced cytotoxicity. Considerable changes in the morphology and adhesion of H460 cells were observed in response to varying NaAR concentrations. NaAR exposure induced DNA damage-mediated apoptosis and Nix accumulation via proteasome inhibition. Nix targets the endoplasmic reticulum (ER), inducing ER stress responses. p62 and Nix were colocalized and their expressions were inversely correlated. Autophagy inhibition upregulated Nix, p62, cell cycle progression gene 1 (CCPG1), heme oxygenase (HO)− 1, and calnexin expression. Nix knockdown decreased the NaAR-induced ER stress and microtubule-associated protein 1 A/1B light-chain 3 (LC3) B-II levels and increased the CCPG1 and calnexin levels. p62 knockdown upregulated Nix, LC3-II, and CCPG1 expressions and the ER stress responses, indicating that p62 regulates Nix levels. Nix downstream pathways were mitigated by Ca2+ chelators. We demonstrate the critical roles of Nix and p62 in ER stress and ER-phagy in response to NaAR. •Arsenite induces ER stress responses and DNA damage in H460 cells.•Nix is upregulated by proteasome inhibition, targeting to the ER.•ER Nix regulates arsenic-induced ER stress response and ER-phagy.•ER Nix regulates ER-phagy through p62 and CCPG1.•NaAR-induced ER stress and ER-phagy is depend on intracellular Ca2+.
ISSN:1382-6689
1872-7077
DOI:10.1016/j.etap.2023.104111