Fig. 2.18 The unfolded protein response and endoplasmic reticulum (ER) stress. The presence of misfolded proteins in the ER is detected by sensors in the ER membrane, such as the kinase IRE-1, which form oligomers that are activated by phosphorylation. This triggers an adaptive unfolded protein response, which can protect the cell from the harmful consequences of the misfolded proteins. When the amount of misfolded proteins is too great to be corrected, excessive activation of ER sensors activates the mitochondrial pathway of apoptosis and the irreparably damaged cell dies; this is also called the terminal unfolded protein response.
Protein misfolding within cells may cause disease by • Cell death as a result of protein misfolding is recognized creating a deficiency of an essential protein or by induc-as a feature of a number of diseases, including the neuing apoptosis (
Table 2.4 ). rodegenerative disorders Alzheimer disease, Hunting • Misfolded proteins often lose their activity and are rapidly ton disease, and Parkinson disease, and may underlie degraded, both of which can contribute to a loss of func-type 2 diabetes as well (
Table 2.4 ). tion. If this function is essential, cellular injury ensues. One important disease in which this occurs is cystic fibro-As discussed later in the chapter, improperly folded sis, which is caused by inherited mutations in a mem-proteins can also accumulate in extracellular tissues, as in brane transport protein that prevent its normal folding. amyloidosis.
Table 2.4 Diseases Caused by Misfolded Proteins
Diseases Caused by Mutant Proteins That Are Degraded, Leading to Their Deficiency
Retinitis pigmentosaRhodopsinAbnormal folding of rhodopsin causes photoreceptor loss and cell death, resulting in blindness
Diseases Caused by Misfolded Proteins That Result From Both ER Stress-Induced Cell Loss and Functional Deficiency of the Protein aSelected illustrative examples of diseases are shown in which protein misfolding is thought to be the major mechanism of functional derangement or cell or tissue injury.CFTR, Cystic fibrosis transmembrane conductance regulator; LDL, low-density lipoprotein.
Exposure of cells to radiation or chemotherapeutic agents, intracellular generation of ROS, and acquisition of mutations may all induce DNA damage, which if severe may trigger apoptotic death. Damage to DNA is sensed by intracellular sentinel proteins, which transmit signals that lead to the accumulation of p53 protein. p53 first arrests the cell cycle (at the G1 phase) to allow the DNA to be repaired before it is replicated (Chapter 6). However, if the damage is too great to be repaired successfully, p53 triggers apoptosis, mainly by stimulating BH3-only sensor proteins that ultimately activate Bax and Bak, proapoptotic members of the Bcl-2 family. When p53 is mutated or absent (as it is in certain cancers), cells with damaged DNA that would otherwise undergo apoptosis survive. In such cells, the DNA damage may result in mutations or DNA rearrangements (e.g., translocations) that lead to neoplastic transformation (Chapter 6).