Targeting EDEM protects against ER stress and improves development and survival in C. elegans.

Danielle A Garsin,Simona Ghenea,Marioara Chiritoiu,Antonio Miranda-Vizuete,Robi Tacutu,Stefana Maria Petrescu

doi:10.1371/journal.pgen.1010069

Abstract

EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins in the endoplasmic reticulum (ER) by accelerating disposal and degradation of misfolded proteins through ER Associated Degradation (ERAD). Although many previous studies reported the role of individual ERAD components especially in cell-based systems, still little is known about the consequences of ERAD dysfunction under physiological and ER stress conditions in the context of a multicellular organism. Here we report the first individual and combined characterization and functional interplay of EDEM proteins in Caenorhabditis elegans using single, double, and triple mutant combinations. We found that EDEM-2 has a major role in the clearance of misfolded proteins from ER under physiological conditions, whereas EDEM-1 and EDEM-3 roles become prominent under acute ER stress. In contrast to SEL-1 loss, the loss of EDEMs in an intact organism induces only a modest ER stress under physiological conditions. In addition, chronic impairment of EDEM functioning attenuated both XBP-1 activation and up-regulation of the stress chaperone GRP78/BiP, in response to acute ER stress. We also show that pre-conditioning to EDEM loss in acute ER stress restores ER homeostasis and promotes survival by activating ER hormesis. We propose a novel role for EDEM in fine-tuning the ER stress responsiveness that affects ER homeostasis and survival.

Highlights

Cells respond to stress stimuli by modulating a wide range of cellular processes to promote survival of the organism
We found that EDEM-2 has a major role in the clearance of misfolded proteins from endoplasmic reticulum (ER) under physiological conditions, whereas EDEM-1 and EDEM-3 roles become prominent under acute ER stress
ER stress and unfolded protein response (UPRER) malfunctions have been implicated in the pathogenesis of neurodegeneration, metabolic and inflammatory diseases as well as tumor progression and diabetes, whereby disturbed ER homeostasis negatively influences the pathology of the disease

Summary

Introduction

Cells respond to stress stimuli by modulating a wide range of cellular processes to promote survival of the organism. Failure to activate an efficient response to stress disturbs organelle homeostasis. Impairment of organelle homeostasis triggers activation of compensatory stress responses such as ER unfolded protein response (UPRER), mitochondrial unfolded protein response (UPRmt), peroxisomal quality control system and autophagy aiming to restore their normal function [1,2]. Misfolded or incompletely folded proteins are recognized by the ER quality control surveillance system and removed from ER to be degraded by the proteasome in a process called ERassociated degradation (ERAD) [3,4,5]. Dysfunctions in ERAD lead to ER stress by overload with defective proteins, which further disrupts ER homeostasis. ER stress has been associated with a wide range of pathologies such as age-related maladies, cancer, metabolic diseases and inflammation [6,7,8,9]

Methods

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Discussion

Conclusion