FBG1 Is the Final Arbitrator of A1AT-Z Degradation

John H Wen; Hsiang Wen; Katherine N Gibson-Corley; Kevin A Glenn

doi:10.1371/journal.pone.0135591

FBG1 Is the Final Arbitrator of A1AT-Z Degradation

PLoS One. 2015 Aug 21;10(8):e0135591. doi: 10.1371/journal.pone.0135591. eCollection 2015.

Authors

John H Wen¹, Hsiang Wen², Katherine N Gibson-Corley³, Kevin A Glenn⁴

Affiliations

¹ Yale University, New Haven, CT, United States of America.
² Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States of America.
³ Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States of America.
⁴ Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States of America; VA Medical Center, Iowa City, IA, United States of America.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Apoptosis Regulatory Proteins / genetics*
Apoptosis Regulatory Proteins / metabolism
Autophagy / genetics*
Beclin-1
Cell Line, Tumor
Disease Models, Animal
Endoplasmic Reticulum / metabolism
Female
Gene Expression Regulation
Half-Life
Hepatocytes / cytology
Hepatocytes / metabolism
Humans
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mice
Mice, Transgenic
Mutation
Proteasome Endopeptidase Complex / metabolism*
Protein Binding
Proteolysis
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
SKP Cullin F-Box Protein Ligases / antagonists & inhibitors
SKP Cullin F-Box Protein Ligases / genetics*
SKP Cullin F-Box Protein Ligases / metabolism
Signal Transduction
Ubiquitination
alpha 1-Antitrypsin / genetics*
alpha 1-Antitrypsin / metabolism
alpha 1-Antitrypsin Deficiency / genetics*
alpha 1-Antitrypsin Deficiency / metabolism
alpha 1-Antitrypsin Deficiency / pathology

Substances

Apoptosis Regulatory Proteins
BECN1 protein, human
Beclin-1
Membrane Proteins
RNA, Small Interfering
alpha 1-Antitrypsin
SKP Cullin F-Box Protein Ligases
Proteasome Endopeptidase Complex

Grants and funding

Veteran Affairs Research Career Development Award to KAG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.