Cargando…

Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells

Viruses alter a multitude of host-cell processes to create a more optimal environment for viral replication. This includes altering metabolism to provide adequate substrates and energy required for replication. Typically, viral infections induce a metabolic phenotype resembling the Warburg effect, w...

Descripción completa

Detalles Bibliográficos
Autores principales: Prusinkiewicz, Martin A., Tu, Jessie, Dodge, Mackenzie J., MacNeil, Katelyn M., Radko-Juettner, Sandi, Fonseca, Gregory J., Pelka, Peter, Mymryk, Joe S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354625/
https://www.ncbi.nlm.nih.gov/pubmed/32503156
http://dx.doi.org/10.3390/v12060610
_version_ 1783558128564961280
author Prusinkiewicz, Martin A.
Tu, Jessie
Dodge, Mackenzie J.
MacNeil, Katelyn M.
Radko-Juettner, Sandi
Fonseca, Gregory J.
Pelka, Peter
Mymryk, Joe S.
author_facet Prusinkiewicz, Martin A.
Tu, Jessie
Dodge, Mackenzie J.
MacNeil, Katelyn M.
Radko-Juettner, Sandi
Fonseca, Gregory J.
Pelka, Peter
Mymryk, Joe S.
author_sort Prusinkiewicz, Martin A.
collection PubMed
description Viruses alter a multitude of host-cell processes to create a more optimal environment for viral replication. This includes altering metabolism to provide adequate substrates and energy required for replication. Typically, viral infections induce a metabolic phenotype resembling the Warburg effect, with an upregulation of glycolysis and a concurrent decrease in cellular respiration. Human adenovirus (HAdV) has been observed to induce the Warburg effect, which can be partially attributed to the adenovirus protein early region 4, open reading frame 1 (E4orf1). E4orf1 regulates a multitude of host-cell processes to benefit viral replication and can influence cellular metabolism through the transcription factor avian myelocytomatosis viral oncogene homolog (MYC). However, E4orf1 does not explain the full extent of Warburg-like HAdV metabolic reprogramming, especially the accompanying decrease in cellular respiration. The HAdV protein early region 1A (E1A) also modulates the function of the infected cell to promote viral replication. E1A can interact with a wide variety of host-cell proteins, some of which have been shown to interact with metabolic enzymes independently of an interaction with E1A. To determine if the HAdV E1A proteins are responsible for reprogramming cell metabolism, we measured the extracellular acidification rate and oxygen consumption rate of A549 human lung epithelial cells with constitutive endogenous expression of either of the two major E1A isoforms. This was followed by the characterization of transcript levels for genes involved in glycolysis and cellular respiration, and related metabolic pathways. Cells expressing the 13S encoded E1A isoform had drastically increased baseline glycolysis and lower maximal cellular respiration than cells expressing the 12S encoded E1A isoform. Cells expressing the 13S encoded E1A isoform exhibited upregulated expression of glycolysis genes and downregulated expression of cellular respiration genes. However, tricarboxylic acid cycle genes were upregulated, resembling anaplerotic metabolism employed by certain cancers. Upregulation of glycolysis and tricarboxylic acid cycle genes was also apparent in IMR-90 human primary lung fibroblast cells infected with a HAdV-5 mutant virus that expressed the 13S, but not the 12S encoded E1A isoform. In conclusion, it appears that the two major isoforms of E1A differentially influence cellular glycolysis and oxidative phosphorylation and this is at least partially due to the altered regulation of mRNA expression for the genes in these pathways.
format Online
Article
Text
id pubmed-7354625
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-73546252020-07-23 Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells Prusinkiewicz, Martin A. Tu, Jessie Dodge, Mackenzie J. MacNeil, Katelyn M. Radko-Juettner, Sandi Fonseca, Gregory J. Pelka, Peter Mymryk, Joe S. Viruses Article Viruses alter a multitude of host-cell processes to create a more optimal environment for viral replication. This includes altering metabolism to provide adequate substrates and energy required for replication. Typically, viral infections induce a metabolic phenotype resembling the Warburg effect, with an upregulation of glycolysis and a concurrent decrease in cellular respiration. Human adenovirus (HAdV) has been observed to induce the Warburg effect, which can be partially attributed to the adenovirus protein early region 4, open reading frame 1 (E4orf1). E4orf1 regulates a multitude of host-cell processes to benefit viral replication and can influence cellular metabolism through the transcription factor avian myelocytomatosis viral oncogene homolog (MYC). However, E4orf1 does not explain the full extent of Warburg-like HAdV metabolic reprogramming, especially the accompanying decrease in cellular respiration. The HAdV protein early region 1A (E1A) also modulates the function of the infected cell to promote viral replication. E1A can interact with a wide variety of host-cell proteins, some of which have been shown to interact with metabolic enzymes independently of an interaction with E1A. To determine if the HAdV E1A proteins are responsible for reprogramming cell metabolism, we measured the extracellular acidification rate and oxygen consumption rate of A549 human lung epithelial cells with constitutive endogenous expression of either of the two major E1A isoforms. This was followed by the characterization of transcript levels for genes involved in glycolysis and cellular respiration, and related metabolic pathways. Cells expressing the 13S encoded E1A isoform had drastically increased baseline glycolysis and lower maximal cellular respiration than cells expressing the 12S encoded E1A isoform. Cells expressing the 13S encoded E1A isoform exhibited upregulated expression of glycolysis genes and downregulated expression of cellular respiration genes. However, tricarboxylic acid cycle genes were upregulated, resembling anaplerotic metabolism employed by certain cancers. Upregulation of glycolysis and tricarboxylic acid cycle genes was also apparent in IMR-90 human primary lung fibroblast cells infected with a HAdV-5 mutant virus that expressed the 13S, but not the 12S encoded E1A isoform. In conclusion, it appears that the two major isoforms of E1A differentially influence cellular glycolysis and oxidative phosphorylation and this is at least partially due to the altered regulation of mRNA expression for the genes in these pathways. MDPI 2020-06-03 /pmc/articles/PMC7354625/ /pubmed/32503156 http://dx.doi.org/10.3390/v12060610 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Prusinkiewicz, Martin A.
Tu, Jessie
Dodge, Mackenzie J.
MacNeil, Katelyn M.
Radko-Juettner, Sandi
Fonseca, Gregory J.
Pelka, Peter
Mymryk, Joe S.
Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells
title Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells
title_full Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells
title_fullStr Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells
title_full_unstemmed Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells
title_short Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells
title_sort differential effects of human adenovirus e1a protein isoforms on aerobic glycolysis in a549 human lung epithelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354625/
https://www.ncbi.nlm.nih.gov/pubmed/32503156
http://dx.doi.org/10.3390/v12060610
work_keys_str_mv AT prusinkiewiczmartina differentialeffectsofhumanadenoviruse1aproteinisoformsonaerobicglycolysisina549humanlungepithelialcells
AT tujessie differentialeffectsofhumanadenoviruse1aproteinisoformsonaerobicglycolysisina549humanlungepithelialcells
AT dodgemackenziej differentialeffectsofhumanadenoviruse1aproteinisoformsonaerobicglycolysisina549humanlungepithelialcells
AT macneilkatelynm differentialeffectsofhumanadenoviruse1aproteinisoformsonaerobicglycolysisina549humanlungepithelialcells
AT radkojuettnersandi differentialeffectsofhumanadenoviruse1aproteinisoformsonaerobicglycolysisina549humanlungepithelialcells
AT fonsecagregoryj differentialeffectsofhumanadenoviruse1aproteinisoformsonaerobicglycolysisina549humanlungepithelialcells
AT pelkapeter differentialeffectsofhumanadenoviruse1aproteinisoformsonaerobicglycolysisina549humanlungepithelialcells
AT mymrykjoes differentialeffectsofhumanadenoviruse1aproteinisoformsonaerobicglycolysisina549humanlungepithelialcells