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. 2020 Jul;35(7):758-767.
doi: 10.1002/tox.22910. Epub 2020 Feb 15.

Silica dust exposure induces autophagy in alveolar macrophages through switching Beclin1 affinity from Bcl-2 to PIK3C3

Pan Yang  1 , Ruirui Song  2 , Ning Li  1 , Kun Sun  1 , Fan Shi  1 , Heliang Liu  1 , Fuhai Shen  1 , Shoufang Jiang  1 , Lin Zhang  3 , Yulan Jin  1
Affiliations

Silica dust exposure induces autophagy in alveolar macrophages through switching Beclin1 affinity from Bcl-2 to PIK3C3

Pan Yang et al. Environ Toxicol. 2020 Jul.

Abstract

Increased deposition of silica dust in pulmonary interstitial tissues leads to silicosis, in which autophagy plays a defensive role in silica dust-associated stress response and cell death. Our previous studies revealed that silica dust exposure contributed to autophagy in pulmonary macrophages in vivo, while the specific regulatory mechanism is still unclear. This study aimed to figure out the regulatory mechanism as well as the role of autophagy in the pathogenesis of experimental silicosis. We used 3-methyladenine (3-MA) and ABT-737 to suppress the expression of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and B cell leukemia/lymphoma 2 (Bcl-2), two critical initiators of autophagy, and detected and evaluated the autophagy in NR8383 cells with or without silica dust exposure. We found that exposure of silica dust increased autophagy in NR8383 cells and elevated the expression of Beclin1 and PIK3C3, but it reduced the expression of Bcl-2. The relationship among Beclin1, PIK3C3, and Bcl-2 were then investigated using immunoprecipitation analysis, and we found that suppression of PIK3C3 and/or Bcl-2 using 3-MA and/or ABT-737 could alter the autophagy induced by silica dust in NR8383 cells, and the complexes of Beclin1/PIK3C3 and Beclin1/Bcl-2 were both downregulated, which may be that inhibition of PIK3C3 and Bcl-2 altered the affinity of Beclin1 with PIK3C3 and Bcl-2 and lead to the silence of PIK3C3 signaling. These findings indicate that silica dust exposure induces autophagy via changing the connectivity of Beclin1 from Bcl-2 to PIK3C3.

Keywords: Bcl-2; Beclin1; PIK3C3; autophagy; silicosis.

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References

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