Alleviating chronic ER stress by p38-Ire1-Xbp1pathway and insulin-associated autophagy in C. elegans neurons.

Liying Guan,Xun Huang,Mei Ding,Yongzhi Yang,Yue Miao,Zhigao Zhan,Javier E Irazoqui

doi:10.1371/journal.pgen.1008704

Abstract

ER stress occurs in many physiological and pathological conditions. However, how chronic ER stress is alleviated in specific cells in an intact organism is an outstanding question. Here, overexpressing the gap junction protein UNC-9 (Uncoordinated) in C. elegans neurons triggers the Ire1-Xbp1-mediated stress response in an age-dependent and cell-autonomous manner. The p38 MAPK PMK-3 regulates the chronic stress through IRE-1 phosphorylation. Overexpressing gap junction protein also activates autophagy. The insulin pathway functions through autophagy, but not the transcription of genes encoding ER chaperones, to counteract the p38-Ire1-Xbp1-mediated stress response. Together, these results reveal an intricate cellular regulatory network in response to chronic stress in a subset of cells in multicellular organism.

Highlights

Proteins destined for secretion or insertion into membranes enter the endoplasmic reticulum (ER) in an unfolded form and generally leave only after they have reached their native states
We designed a genetic system in the nematode C. elegans, which allows us to induce ER stress in specific cells, without drug treatment or any other external stimuli, and to monitor the stress response
To test whether ER stress response and its regulators are required to achieve this proper localization in UNC-9 over-expressing worms, we firstly examined the hsp-4 induction. hsp-4 encodes the worm homolog of the ER chaperone protein Bip and its transcription is strongly induced by the stress response [9]

Summary

Introduction

Proteins destined for secretion or insertion into membranes enter the endoplasmic reticulum (ER) in an unfolded form and generally leave only after they have reached their native states. A secretory cell may experience dramatic variations in the flux of new proteins through its ER in response to changes in demand. Disruption of the balance between secretory protein synthesis and the folding capacity of the ER activates a signaling network called UPR (the Unfolded Protein Response) in an attempt to maintain homeostasis [1]. The UPR reduces protein translation, increases expression of ER chaperones and enzymes to facilitate protein folding, and clears misfolded proteins for degradation [1]. Extensive or prolonged UPR activity signals that the accumulation of misfolded proteins has overwhelmed the compensatory mechanisms of the UPR, and an apoptotic response may be elicited [2]. The UPR can serve either as an apoptotic executor or as a cytoprotector, depending on the cellular context

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