p62/SQSTM1 accumulation due to degradation inhibition and transcriptional activation plays a critical role in silica nanoparticle-induced airway inflammation via NF-κB activation

Author:

Wu Yifan,Jin Yang,Sun Tianyu,Zhu Piaoyu,Li Jinlong,Zhang Qinglin,Wang Xiaoke,Jiang Junkang,Chen Gang,Zhao Xinyuan

Abstract

Abstract Background Most nanoparticles (NPs) reportedly block autophagic flux, thereby upregulating p62/SQSTM1 through degradation inhibition. p62 also acts as a multifunctional scaffold protein with multiple domains, and is involved in various cellular processes. However, the autophagy substrate-independent role of p62 and its regulation at the transcriptional level upon NPs exposure remain unclear. Results In this work, we exposed BEAS-2b cells and mice to silica nanoparticles (SiNPs), and found that SiNPs increased p62 protein levels in vivo and vitro. Then, we further explored the role and mechanism of SiNPs-stimulated p62 in vitro, and found that p62 degradation was inhibited due to autophagic flux blockade. Mechanistically, SiNPs blocked autophagic flux through impairment of lysosomal capacity rather than defective autophagosome fusion with lysosomes. Moreover, SiNPs stimulated translocation of NF-E2-related factor 2 (Nrf2) to the nucleus from the cytoplasm, which upregulated p62 transcriptional activation through direct binding of Nrf2 to the p62 promoter. Nrf2 siRNA dramatically reduced both the mRNA and protein levels of p62. These two mechanisms led to p62 protein accumulation, thus increasing interleukin (IL)-1 and IL-6 expression. SiNPs activated nuclear factor kappa B (NF-κB), and this effect could be alleviated by p62 knockdown. Conclusion SiNPs caused accumulation of p62 through both pre- and post-translational mechanisms, resulting in airway inflammation. These findings improve our understanding of SiNP-induced pulmonary damage and the molecular targets available to mitigate it.

Funder

Large Instruments Open Foundation of Nantong University

National Natural Science Foundation of China

Nantong Jiangsu scientific research project

Postgraduate Research & Practice Innovation Program of Jiangsu Province

Scientific Research Project of Wuxi Health and Family Planning Commission

The Yong Medical Talents of wuxi

Qinglan Project of Jiangsu Province of China

Publisher

Springer Science and Business Media LLC

Subject

Pharmaceutical Science,Applied Microbiology and Biotechnology,Biomedical Engineering,Molecular Medicine,Medicine (miscellaneous),Bioengineering

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