Document Type

Article

Peer Reviewed

1

Publication Date

8-21-2015

NLM Title Abbreviation

PLoS One

Journal/Book/Conference Title

PLoS One

PubMed ID

26295339

DOI of Published Version

10.1371/journal.pone.0135591

Abstract

Alpha-1 antitrypsin deficiency is the leading cause of childhood liver failure and one of the most common lethal genetic diseases. The disease-causing mutant A1AT-Z fails to fold correctly and accumulates in the endoplasmic reticulum (ER) of the liver, resulting in hepatic fibrosis and hepatocellular carcinoma in a subset of patients. Furthermore, A1AT-Z sequestration in hepatocytes leads to a reduction in A1AT secretion into the serum, causing panacinar emphysema in adults. The purpose of this work was to elucidate the details by which A1AT-Z is degraded in hepatic cell lines. We identified the ubiquitin ligase FBG1, which has been previously shown to degrade proteins by both the ubiquitin proteasome pathway and autophagy, as being key to A1AT-Z degradation. Using chemical and genetic approaches we show that FBG1 degrades A1AT-Z through both the ubiquitin proteasome system and autophagy. Overexpression of FBG1 decreases the half-life of A1AT-Z and knocking down FBG1 in a hepatic cell line, and in mice results in an increase in ATAT. Finally, we show that FBG1 degrades A1AT-Z through a Beclin1-dependent arm of autophagy. In our model, FBG1 acts as a safety ubiquitin ligase, whose function is to re-ubiquitinate ER proteins that have previously undergone de-ubiquitination to ensure they are degraded.

Keywords

OAfund

Journal Article Version

Version of Record

Published Article/Book Citation

Wen JH, Wen H, Gibson-Corley KN, Glenn KA (2015) FBG1 Is the Final Arbitrator of A1AT-Z Degradation. PLoS ONE 10(8): e0135591. doi:10.1371/journal.pone.0135591

Rights

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons 1.0 Public Domain Dedication.

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URL

https://ir.uiowa.edu/internalmedicine_pubs/13