Chapter 5 - Proteotoxicity and endoplasmic reticulum stress-mediated cell death

Abstract

Proteotoxicity is defined as irreparable damage to the cell that is caused by an accumulation of impaired and misfolded proteins. Uncontrolled or severe proteotoxicity will ultimately result in cell death. The endoplasmic reticulum (ER), which controls the synthesis, folding, sorting, and transportation of over one-third of cellular proteins, is an essential organelle for regulating proteotoxicity. Either the increase of the damaged/misfolded protein load or the reduction of ER folding capacity could disrupt ER homeostasis and induce ER stress. Cells utilize a series of protective actions to restore ER homeostasis, including the induction of a coordinated adaptive program termed the Unfolded Protein Response (UPR). UPR helps to relieve ER stress by increasing the protein folding capacity of the ER and by promoting the ER-Associated Degradation (ERAD) of damaged/misfolded protein. Proteins that are not cleared by ERAD are transferred to quality control autophagy. It is well documented that ER stress is involved in the initiation and progression of various types of health problems, including neurodegeneration, cancer, muscle degeneration, cardiovascular disease, and autoimmune disorders. It is important to characterize the underlying mechanisms of ER stress that contribute to these diseases and to identify potential targets for their prevention and treatment. This chapter will introduce the signaling elements in ER stress pathways and crucial factors that regulate ER homeostasis, followed by a discussion of the mechanisms by which these factors or processes induce ER stress-mediated cell death. Subsequently, ER stress-related diseases and the potential targets for their treatment will be discussed, as well as the drugs that have been developed to target these disorders. Finally, this chapter will pose suggestions for future research directions.