The molecular mechanism by which silica nanoparticles (SiNPs) cause cellular apoptosis in the respiratory system is unclear. Silent mating type information regulation 2 homolog 1 (SIRT1), an NAD+-dependent deacetylase, mediates the pulmonary damage associated with several environmental stimuli. However, the SIRT1 response to SiNP exposure and its role in SiNP-triggered pulmonary toxicity remains unknown. Here, SiNPs were found to downregulate nuclear rather than cytosolic SIRT1 protein levels in human bronchial epithelial cells (BEAS-2b). They did not affect SIRT1 gene expression but accelerated SIRT1 protein degradation via c-Jun N-terminal kinase (JNK) activation. SiNP-mediated SIRT1 suppression markedly increased tumour protein 53 (p53) acetylation and cytoplasmic localisation, leading to the release of cytochrome c from mitochondria to the cytosol. SIRT1 overexpression dramatically decreased p53 acetylation and its cytoplasmic localisation, and this was accompanied by attenuated apoptosis in SiNP-exposed cells. Finally, SiNPs suppressed SIRT1 and stimulated apoptosis in the lung tissues of mice. In summary, SiNPs downregulate nuclear SIRT1 via JNK activation-mediated protein degradation, which leads to apoptosis via p53 acetylation and cytoplasmic localisation. These findings improve our understanding of SiNP-induced pulmonary damage and molecular targets to antagonise it.
Keywords: Apoptosis; Cytoplasmic localisation; Pulmonary damage; SIRT1 suppression; Silica nanoparticle; p53 Acetylation.
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