The Function of Drosophila USP14 in Endoplasmic Reticulum Stress and Retinal Degeneration in a Model for Autosomal Dominant Retinitis Pigmentosa

Jung-Eun Park,Kyunggon Kim,Thị Xuân Thùy Trần,Nayoung Park,Min-Ji Kang,Jeonghun Yeom

doi:10.3390/biology9100332

Jung-Eun Park, Kyunggon Kim + Show 4 more

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https://doi.org/10.3390/biology9100332

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Journal: Biology	Publication Date: Oct 12, 2020
Citations: 2	License type: CC BY 4.0

Affiliation: Asan Medical Center, University of Ulsan, Ulsan College

Abstract

Simple SummaryThe present study shows the role of Drosophila USP14 under ER stress and ER stress related disease, autosomal dominant retinitis pigmentosa. Drosophila USP14 protects cell from ER stress triggered by ER stress-causing chemicals Drosophila S2 cells and suppresses the retinal degeneration in disease model for retinitis pigmentosa by regulating the stability of Rhodopsin-1. This study also indicates the dynamic reorganization of proteasome complex under ER stress. The modulation of USP14 could be a potential therapeutic strategy for treating the diseases associated with protein folding. Endoplasmic reticulum (ER) stress and its adaptive cellular response, the unfolded protein response (UPR), are involved in various diseases including neurodegenerative diseases, metabolic diseases, and even cancers. Here, we analyzed the novel function of ubiquitin-specific peptidase 14 (USP14) in ER stress. The overexpression of Drosophila USP14 protected the cells from ER stress without affecting the proteasomal activity. Null Hong Kong (NHK) and alpha-1-antitrypsin Z (ATZ) are ER-associated degradation substrates. The degradation of NHK, but not of ATZ, was delayed by USP14. USP14 restored the levels of rhodopsin-1 protein in a Drosophila model for autosomal dominant retinitis pigmentosa and suppressed the retinal degeneration in this model. In addition, we observed that proteasome complex is dynamically reorganized in response to ER stress in human 293T cells. These findings suggest that USP14 may be a therapeutic strategy in diseases associated with ER stress.

Highlights

The endoplasmic reticulum (ER) is a major organelle in which membrane and secretory proteins are synthesized and folded properly
Endoplasmic reticulum (ER) stress is closely associated with the ubiquitin-proteasome system that acts via ER-associated degradation (ERAD)
To determine whether ubiquitin-specific peptidase 14 (USP14) regulates the levels of ER stress, we first overexpressed Drosophila

Summary

Introduction

The endoplasmic reticulum (ER) is a major organelle in which membrane and secretory proteins are synthesized and folded properly. When the rate of protein synthesis exceeds the folding capacity of the ER under certain conditions, misfolded or unfolded proteins accumulate in the ER [1] To overcome this stress, cells activate a signaling pathway referred to as unfolded protein response (UPR). Biology 2020, 9, 332 kinase (PKR)-like ER kinase (PERK) These three sensors trigger transcriptional activation mediated by three distinct transducers, spliced X-Box Binding Protein 1 (sXBP1), cleaved ATF6, and ATF4, respectively. These proteins trigger the transcription of genes including those encoding chaperones and ER-associated degradation (ERAD) pathway to restore ER function [2,3,4]. When ER homeostasis cannot be restored, the cell death program is activated, resulting in the development of various diseases, including neurodegenerative disease, retinitis pigmentosa, and diabetes

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