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Viral infection kills (red) cells that have adapted to the expression of a misfolded protein (right).

Cells adjust to cope with long-term stress, according to Bridges et al. (page 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-C^exon4 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-C^exon4. Instead, cells prevented their own death by up-regulating the NF-B 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-C^exon4 died, whereas infected cells expressing normal SP-C survived. The authors propose that mutant cells max out their proteosome capacity to degrade SP-C^exon4, 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.

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C

James P. Bridges, Yan Xu, Cheng-Lun Na, Hector R. Wong, and Timothy E. Weaver
J. Cell Biol. 2006 172: 395-407. [Abstract] [Full Text] [PDF]

This Article PDF (Full Text) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Related Collections Related Article Social Bookmarking                      What's this?