In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences

Abstract

SummaryDisturbances to the balance of protein synthesis, folding and secretion in the endoplasmic reticulum (ER) induce stress and thereby the ER stress signaling (ERSS) response, which alleviates this stress. In this Commentary, we review the emerging idea that ER stress caused by abnormal physiological conditions and/or mutations in genes that encode client proteins of the ER is a key factor underlying different developmental processes and the pathology of diverse diseases, including diabetes, neurodegeneration and skeletal dysplasias. Recent studies in mouse models indicate that the effect of ERSS in vivo and the nature of the cellular strategies induced to ameliorate pathological ER stress are crucial factors in determining cell fate and clinical disease features. Importantly, ERSS can affect cellular proliferation and the differentiation program; cells that survive the stress can become 'reprogrammed' or dysfunctional. These cellautonomous adaptation strategies can generate a spectrum of context-dependent cellular consequences, ranging from recovery to death. Secondary effects can include altered cell-extracellular-matrix interactions and non-cell-autonomous alteration of paracrine signaling, which contribute to the final phenotypic outcome. Recent reports showing that ER stress can be alleviated by chemical compounds suggest the potential for novel therapeutic approaches. (1) Physiological ER stress during development is mild and controllable. The cell can recover from and/or adapt to the protein-folding stress; it can also differentiate into a specialized cell type in a manner that depends on components of ERSS and appropriate developmental signals. (2) In severe pathological ER stress, ERSS is initially an adaptive response, but, if stress remains unresolved, perhaps because of continuous and/or cyclical expression of mutant protein, it can lead to interference with developmental signals and disruption of cellular gene expression patterns. The cell can then display altered proliferation and differentiation status, and become dysfunctional. (3) Under conditions of extreme stress, an apoptotic signal is triggered and becomes dominant, leading to cell death. This can occur through excessive production of reactive oxygen species (ROS) caused by enhanced protein-folding activity, which relates to levels of CHOP, GADD34 and ERO1 expression. Journal of Cell Science Attenuation of translationOne of the early responses to ER stress is the modulation of translation, a highly conserved adaptation mechanism (Yamasaki and Anderson, 2008). Phosphorylation of eukaryotic initiation factor 2 (eIF2) by PERK reduces protein translation and shifts the translation machinery to favor alternative modes of initiation, including selective translation of activating transcription factor 4 (ATF4) . Phosphorylated eIF2 also activates the conversion of microtubule-associated protein 1 light chain 3 (LC3-I), an essential protein for autophagy, to LC3-II and hence promotes autophagosome formation Kouroku et al., 2007), as well as t...

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