395), but the adjustments make them ultrasensitive to a second stress. The timing of subsequent insults might explain the variation seen in the onset of a variety of diseases.
One disease with a highly variable age of onset is interstitial lung disease (ILD), which can be caused by mutations in the gene for the SP-C lung surfactant protein. The SP-CΔexon4 mutant version accumulates as a misfolded protein in the ER. Using this mutation to study the ER unfolded protein response (UPR), Bridges et al. discovered that cells deal with chronic stress and acute problems much differently.
Acute UPR activation causes cells to slow general translation, make more chaperones, and up-regulate the proteosome to alleviate ER stress. But the authors found none of these responses in cell lines that stably expressed SP-CΔexon4. Instead, cells prevented their own death by up-regulating the NF-κB pathway.
Although the cells survived, the attenuation of the UPR was detrimental to their reaction to secondary insults. When also infected with the respiratory syncytial virus (RSV), cells expressing SP-CΔexon4 died, whereas infected cells expressing normal SP-C survived. The authors propose that mutant cells max out their proteosome capacity to degrade SP-CΔexon4, and the extra load from the virus tips them over the edge.
Some ILD patients are also infected with RSV or influenza virus. Variability in the onset of this and many other diseases might thus be explained by the timing and severity of later insults, including various pathogenic infections.