Abstract
Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and function depend on the active secretion of mature proteins from a variety of cell types in the heart, a process that requires an intact ER environment for efficient protein folding and trafficking to the secretory pathway. As a consequence of ER stress, most protein secretion by the ER secretory pathway is decreased. Strikingly, there is a select group of proteins that are secreted in greater quantities during ER stress. ER stress resulting from the dysregulation of ER Ca2+ levels, for instance, stimulates the secretion of Ca2+-binding ER chaperones, especially GRP78, GRP94, calreticulin, and mesencephalic astrocyte-derived neurotrophic factor (MANF), which play a multitude of roles outside the cell, strongly depending on the cell type and tissue. Here we review current insights in ER stress-induced secretion of proteins, particularly from the heart, and highlight the extracellular functions of these proteins, ranging from the augmentation of cardiac cell viability to the modulation of pro- and anti-apoptotic, oncogenic, and immune-stimulatory cell signaling, cell invasion, extracellular proteostasis, and more. Many of the roles of ER stress-induced protein secretion remain to be explored in the heart. This article is part of a special issue entitled “The Role of Proteostasis Derailment in Cardiac Diseases.”
Highlights
Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the endoplasmic reticulum (ER), for example ischemia, and is a common event in various human pathologies, including the diseased heart
ER stress resulting from the dysregulation of ER Ca2+ levels, for instance, stimulates the secretion of Ca2+ -binding ER chaperones, especially GRP78, GRP94, calreticulin, and mesencephalic astrocyte-derived neurotrophic factor (MANF), which play a multitude of roles outside the cell, strongly depending on the cell type and tissue
This study demonstrated for the first time that GRP78 secreted as a result of ER stress can protect cardiac myocytes in a Cripto-1 growth factor (Cripto)-dependent manner
Summary
The heart is made of highly differentiated cells that must communicate with each other and with cells outside the heart to facilitate normal organ development and function [1]. Proteins actively secreted from cardiac cells are called cardiokines [3,4] and are released via the classical [5] or non-classical [6] secretory pathways (Figure 1). The last step of classical protein secretion can be constitutive or regulated, depending on whether the secretory vesicles fuse with the plasma membrane directly after packaging, or whether they are stored until the appropriate stimulus activates their secretion (Figure 1; Classical secretion). Non-classical secretion, on the other hand, describes ER-/Golgi-independent protein trafficking through various kinds of either vesicle- or nonvesicle-mediated pathways [16]. S100A1, a cardiac myocyte-specific member of the EF-hand Ca2+ -binding S100 protein family, is a regulator of cardiac myocyte function and is secreted via the non-classical secretory pathway during myocardial infarction. Considering the role of the ER in classical protein secretion, the status of the ER is an important determinant of cardiac function
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