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Nov 26, 2015;5 17127.

Downregulation of the small GTPase SAR1A: a key event underlying alcohol-induced Golgi fragmentation in hepatocytes.

Armen Petrosyan, Pi-Wan Cheng, Dahn L Clemens, Carol A Casey
Author Information
  1. Armen Petrosyan: Department of Biochemistry and Molecular Biology, College of Medicine, Omaha, NE, USA.
  2. Pi-Wan Cheng: Department of Biochemistry and Molecular Biology, College of Medicine, Omaha, NE, USA.
  3. Dahn L Clemens: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
  4. Carol A Casey: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
PMID: 26607390 DOI: 10.1038/srep17127

Abstract

The hepatic asialoglycoprotein receptor (ASGP-R) is posttranslationally modified in the Golgi en route to the plasma membrane, where it mediates clearance of desialylated serum glycoproteins. It is known that content of plasma membrane-associated ASGP-R is decreased after ethanol exposure, although the mechanisms remain elusive. Previously, we found that formation of compact Golgi requires dimerization of the largest Golgi matrix protein giantin. We hypothesize that ethanol-impaired giantin function may be related to altered trafficking of ASGP-R. Here we report that in HepG2 cells expressing alcohol dehydrogenase and hepatocytes of ethanol-fed rats, ethanol metabolism results in Golgi disorganization. This process is initiated by dysfunction of SAR1A GTPase followed by altered COPII vesicle formation and impaired Golgi delivery of the protein disulfide isomerase A3 (PDIA3), an enzyme that catalyzes giantin dimerization. Additionally, we show that SAR1A gene silencing in hepatocytes mimics the effect of ethanol: dedimerization of giantin, arresting PDIA3 in the endoplasmic reticulum (ER) and large-scale alterations in Golgi architecture. Ethanol-induced Golgi fission has no effect on ER-to-Golgi transportation of ASGP-R, however, it results in its deposition in cis-medial-, but not trans-Golgi. Thus, alcohol-induced deficiency in COPII vesicle formation predetermines Golgi fragmentation which, in turn, compromises the Golgi-to-plasma membrane transportation of ASGP-R.

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Grants

  1. I01 BX000985/BLRD VA
  2. IK6 BX004853/BLRD VA
  3. K01 AA022979/NIAAA NIH HHS
  4. K01AA022979-01/NIAAA NIH HHS

MeSH Term

Alcohol Dehydrogenase
Animals
Asialoglycoprotein Receptor
COP-Coated Vesicles
Down-Regulation
Endoplasmic Reticulum
Ethanol
Gene Silencing
Golgi Apparatus
Golgi Matrix Proteins
Hep G2 Cells
Hepatocytes
Humans
Liver
Membrane Proteins
Metabolome
Mice
Models, Biological
Monomeric GTP-Binding Proteins
Phenotype
Protein Disulfide-Isomerases
Protein Multimerization
Rats

Chemicals

Asialoglycoprotein Receptor
Golgi Matrix Proteins
Membrane Proteins
macrogolgin
Ethanol
Alcohol Dehydrogenase
SAR1A protein, human
Monomeric GTP-Binding Proteins
Protein Disulfide-Isomerases
PDIA3 protein, human
Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.
Article has an altmetric score of 2

Word Cloud

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