JNK activation-mediated nuclear SIRT1 protein suppression contributes to silica nanoparticle-induced pulmonary damage via p53 acetylation and cytoplasmic localisation.

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.