Molecular logic of the endoplasmic reticulum stress signal pathways: the system of Unfolded Protein Response

Abstract

Endoplasmic reticulum (ER) is the central organelle of a eukaryotic cell, it provides the synthesis and maturation of the majority of secretory and transmembrane proteins. The intensity of ER-related protein synthesis and ER loading varies in different cell types and depends on the cell microenvironment, physiological state of the cells, the stage of cellular differentiation. Quality control of transmembrane and secretory proteins in ER is a high precision process. The proteins with non-native conformations which are difficult or energetically disadvantageous to refold undergo ubiquitin-dependent proteolytic degradation. Homeostatic control of protein maturation in ER is mediated by a system of interconnected signaling pathways represented sensors located in the lumen of the ER, and effectors, that transmit information to other cell compartments. This system of intracellular signaling pathways play an important role in the endoplasmic reticulum stress and initiates a complex cellular response to the proteins with non-native conformations (Unfolded Protein Response, UPR). However, if homeostasis is not restored, cell death is triggered via apoptosis, which is a supracellular level adaptation mechanism that protects the tissues and the whole organism from dysfunctional and potentially immunogenic unfolded proteins. Malfunctions of the UPR, as well as ER-associated protein degradation (ERAD) process contribute to the development of many diseases: cardiovascular, neurodegenerative, endocrine diseases, autoimmune. The list of factors and mechanisms involved in ER stress is constantly updated, which is a result of significant attention to ER stress as a typical pathophysiological process that forms the basis of many diseases.