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Sensing and Signaling Cell Stress

Module: 
2
Section: 
C

Instructor: Christopher Nicchitta
Summary: The biological consequences of protein misfolding are often lethal and “proteinopathies” (diseases of protein folding), including Alzheimer’s, Parkinson’s, Type II diabetes, cystic fibrosis, and prion diseases, now number in the hundreds. Given the potentially lethal outcome of protein misfolding, the question of how cells respond to the accumulation of unfolded proteins has proven to be both critically important and fascinating.
Many forms of cell stress, including glucose deprivation and oxidative stress, disrupt protein folding through effects on post-translational modifications of secretory and integral membrane proteins. These experimental findings provided a useful entry point for investigations into the cellular response to the accumulation of unfolded proteins. In this module we will discuss, in depth, landmark papers that report the discovery of the Unfolded Protein Response (UPR), an endoplasmic reticulum-based regulatory response to the accumulation of unfolded proteins. We will trace the field from its inception - how was a cellular response to the accumulation of unfolded proteins discovered? - to current research, which has identified critical roles for the UPR in development and human disease.

Readings: 

Molecular Biology of the Cell, Alberts et al. - Chapter 12 (Intracellular compartments and protein sorting)

Braakman I., and Bulleid, N.J. (2011) Protein Folding and Modification in the Mammalian Endoplasmic Reticulum. Annu Rev Biochem. 80:71-99.