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ERAD and autophagy cooperatively facilitate clearance of aggregation‐prone mutant Surfactant Protein C

We have previously shown that mutations within the BRICHOS domain of Surfactant Protein C (SP‐C), a conserved C‐terminal region of ~100 amino acids found in a number of degenerative disease‐related proteins, lead to UPR activation, cytosolic aggregation, and activation of caspase‐mediated apoptotic pathways. We hypothesized that in addition to upregulation of quality control mechanisms, SP‐C BRICHOS mutants would induce autophagy as a means of cytoprotection. To study this, A549 and HEK293 cells were transfected with human SP‐CΔexon4 mutant. Expression induced autophagosome formation, assessed by detection of LC3 isoform conversion, and by alteration of the intracellular localization of GFP‐tagged LC3. These results were also observed in primary human alveolar type II cells. Inhibition of either the 26S proteasome with MG‐132, or autophagy by 3‐methyladenine resulted in a significant increase in expression levels of mutant SP‐C, suggesting both pathways play a prominent role in mutant clearance. Inhibition of autophagy in cells expressing SP‐CΔexon4 also led to pronounced Caspase 3 activation, while augmentation of autophagy through rapamycin treatment enhanced the clearance of mutant protein. These results indicate that macroautophagy is important for lung epithelial cell homeostasis via its participation in quality control responses activated by aggregation‐prone BRICHOS mutants.