ER stress causes widespread protein aggregation and prion formation.

Norfadilah Hamdan,Chris M Grant,Paraskevi Kritsiligkou

doi:10.1083/jcb.201612165

Norfadilah Hamdan, Chris M Grant + Show 1 more

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https://doi.org/10.1083/jcb.201612165

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Journal: The Journal of cell biology	Publication Date: Jun 19, 2017
Citations: 63	License type: CC BY 4.0

Affiliation: University of Manchester

Abstract

Disturbances in endoplasmic reticulum (ER) homeostasis create a condition termed ER stress. This activates the unfolded protein response (UPR), which alters the expression of many genes involved in ER quality control. We show here that ER stress causes the aggregation of proteins, most of which are not ER or secretory pathway proteins. Proteomic analysis of the aggregated proteins revealed enrichment for intrinsically aggregation-prone proteins rather than proteins which are affected in a stress-specific manner. Aggregation does not arise because of overwhelming proteasome-mediated degradation but because of a general disruption of cellular protein homeostasis. We further show that overexpression of certain chaperones abrogates protein aggregation and protects a UPR mutant against ER stress conditions. The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress.

Highlights

The ability to maintain the balance between protein biogenesis, folding, trafficking, and degradation in the face of changing conditions is essential for viability in all eukaryotic cells
Protein aggregation was analyzed in mutants deficient in the unfolded protein response (UPR) (HAC1 and IRE1) or endoplasmic reticulum (ER)-associated degradation (ERAD) (HRD1 and DOA10) and in cells exposed to tunicamycin (Tm) or DTT to promote ER stress (Cox et al, 1993; Kohno et al, 1993)
To confirm that protein aggregation occurs during ER stress, aggregates were purified using an established biochemical approach (Tomoyasu et al, 2001; Jang et al, 2004; Rand and Grant, 2006; Koplin et al, 2010)

Summary

Introduction

The ability to maintain the balance between protein biogenesis, folding, trafficking, and degradation in the face of changing conditions is essential for viability in all eukaryotic cells. Protein aggregation was analyzed in mutants deficient in the UPR (HAC1 and IRE1) or ERAD (HRD1 and DOA10) and in cells exposed to tunicamycin (Tm) or DTT to promote ER stress (Cox et al, 1993; Kohno et al, 1993).

Results

Conclusion