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Degradation of Human PDZ-Proteins by Human Alphapapillomaviruses Represents an Evolutionary Adaptation to a Novel Cellular Niche.

Van Doorslaer K, DeSalle R, Einstein MH, Burk RD - PLoS Pathog. (2015)

Bottom Line: The relationship between both traits (oncogenicity and PDZ degradation potential) is best explained by a model in which the potential to degrade PDZ proteins was acquired prior to the oncogenic phenotype.This suggests that HPV E6 directed degradation of PDZ-proteins represents an ancient ecological niche adaptation.Phylogenetic modeling indicates that this phenotype is not specifically correlated with oncogenic risk, but may act as an enabling phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.

ABSTRACT
In order to complete their life cycle, papillomaviruses have evolved to manipulate a plethora of cellular pathways. The products of the human Alphapapillomavirus E6 proteins specifically interact with and target PDZ containing proteins for degradation. This viral phenotype has been suggested to play a role in viral oncogenesis. To analyze the association of HPV E6 mediated PDZ-protein degradation with cervical oncogenesis, a high-throughput cell culture assay was developed. Degradation of an epitope tagged human MAGI1 isoform was visualized by immunoblot. The correlation between HPV E6-induced degradation of hMAGI1 and epidemiologically determined HPV oncogenicity was evaluated using a Bayesian approach within a phylogenetic context. All tested oncogenic types degraded the PDZ-containing protein hMAGI1d; however, E6 proteins isolated from several related albeit non-oncogenic viral types were equally efficient at degrading hMAGI1. The relationship between both traits (oncogenicity and PDZ degradation potential) is best explained by a model in which the potential to degrade PDZ proteins was acquired prior to the oncogenic phenotype. This analysis provides evidence that the ancestor of both oncogenic and non-oncogenic HPVs acquired the potential to degrade human PDZ-containing proteins. This suggests that HPV E6 directed degradation of PDZ-proteins represents an ancient ecological niche adaptation. Phylogenetic modeling indicates that this phenotype is not specifically correlated with oncogenic risk, but may act as an enabling phenotype. The role of PDZ protein degradation in HPV fitness and oncogenesis needs to be interpreted in the context of Alphapapillomavirus evolution.

No MeSH data available.


Related in: MedlinePlus

Presence of C-terminal PDZ binding motif is correlated with phylogenetic classification.The Bayesian phylogenetic tree is constructed based on the E6 nucleotide sequences of all known human Alphapapillomaviruses. HPV8, a Betapapillomaviruses was used to root the tree. The solid branches indicate the optimized branch lengths. Dotted lines were added to the branches to facilitate visual inspection of the tree. Epidemiological classification divides the tree into two main clades (“high-risk” vs.”low-risk”). Oncogenic papillomavirus types are colored red (classification based on [7]). Posterior probability values are indicated using symbols at the nodes (triangle = 1; rectangle > 0.95; circle>0.90; diamond >0.80). The numbers to the right indicate the different viral species within the genus Alphapapillomaviruses. The sequence of the six C-terminal residues constituting a putative type 1 PBM is indicated following the virus name. A dash (“-“) indicates the absence of a residue at that position. Numbers above the sequences allow for easy identification of landmark residues as in [42]. Viruses in Bold were selected for the in vivo analyses.
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ppat.1004980.g001: Presence of C-terminal PDZ binding motif is correlated with phylogenetic classification.The Bayesian phylogenetic tree is constructed based on the E6 nucleotide sequences of all known human Alphapapillomaviruses. HPV8, a Betapapillomaviruses was used to root the tree. The solid branches indicate the optimized branch lengths. Dotted lines were added to the branches to facilitate visual inspection of the tree. Epidemiological classification divides the tree into two main clades (“high-risk” vs.”low-risk”). Oncogenic papillomavirus types are colored red (classification based on [7]). Posterior probability values are indicated using symbols at the nodes (triangle = 1; rectangle > 0.95; circle>0.90; diamond >0.80). The numbers to the right indicate the different viral species within the genus Alphapapillomaviruses. The sequence of the six C-terminal residues constituting a putative type 1 PBM is indicated following the virus name. A dash (“-“) indicates the absence of a residue at that position. Numbers above the sequences allow for easy identification of landmark residues as in [42]. Viruses in Bold were selected for the in vivo analyses.

Mentions: E6 sequences representing all viral types within the genus Alphapapillomavirus were downloaded from the PaVE database (http://pave.niaid.nih.gov/#home)[31]. The DNA sequences were translated to amino acids and aligned using MAFFT (the L-INS-I algorithm was used) [32], and the corresponding nucleotide coding regions were aligned within the Seaview program [33]. Bayesian tree reconstruction was performed using MrBayes [34,35] while implementing the GTR+I+G model (as selected by Jmodeltest2 [36,37]; S1 Table). To ensure the most efficient Bayesain analysis the convergence of the Markov chain Monte Carlo (MCMC) chains was explored graphically using AWTY [38]. The final posterior sample of trees is summarized as a majority rule consensus tree in Fig 1.


Degradation of Human PDZ-Proteins by Human Alphapapillomaviruses Represents an Evolutionary Adaptation to a Novel Cellular Niche.

Van Doorslaer K, DeSalle R, Einstein MH, Burk RD - PLoS Pathog. (2015)

Presence of C-terminal PDZ binding motif is correlated with phylogenetic classification.The Bayesian phylogenetic tree is constructed based on the E6 nucleotide sequences of all known human Alphapapillomaviruses. HPV8, a Betapapillomaviruses was used to root the tree. The solid branches indicate the optimized branch lengths. Dotted lines were added to the branches to facilitate visual inspection of the tree. Epidemiological classification divides the tree into two main clades (“high-risk” vs.”low-risk”). Oncogenic papillomavirus types are colored red (classification based on [7]). Posterior probability values are indicated using symbols at the nodes (triangle = 1; rectangle > 0.95; circle>0.90; diamond >0.80). The numbers to the right indicate the different viral species within the genus Alphapapillomaviruses. The sequence of the six C-terminal residues constituting a putative type 1 PBM is indicated following the virus name. A dash (“-“) indicates the absence of a residue at that position. Numbers above the sequences allow for easy identification of landmark residues as in [42]. Viruses in Bold were selected for the in vivo analyses.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4472669&req=5

ppat.1004980.g001: Presence of C-terminal PDZ binding motif is correlated with phylogenetic classification.The Bayesian phylogenetic tree is constructed based on the E6 nucleotide sequences of all known human Alphapapillomaviruses. HPV8, a Betapapillomaviruses was used to root the tree. The solid branches indicate the optimized branch lengths. Dotted lines were added to the branches to facilitate visual inspection of the tree. Epidemiological classification divides the tree into two main clades (“high-risk” vs.”low-risk”). Oncogenic papillomavirus types are colored red (classification based on [7]). Posterior probability values are indicated using symbols at the nodes (triangle = 1; rectangle > 0.95; circle>0.90; diamond >0.80). The numbers to the right indicate the different viral species within the genus Alphapapillomaviruses. The sequence of the six C-terminal residues constituting a putative type 1 PBM is indicated following the virus name. A dash (“-“) indicates the absence of a residue at that position. Numbers above the sequences allow for easy identification of landmark residues as in [42]. Viruses in Bold were selected for the in vivo analyses.
Mentions: E6 sequences representing all viral types within the genus Alphapapillomavirus were downloaded from the PaVE database (http://pave.niaid.nih.gov/#home)[31]. The DNA sequences were translated to amino acids and aligned using MAFFT (the L-INS-I algorithm was used) [32], and the corresponding nucleotide coding regions were aligned within the Seaview program [33]. Bayesian tree reconstruction was performed using MrBayes [34,35] while implementing the GTR+I+G model (as selected by Jmodeltest2 [36,37]; S1 Table). To ensure the most efficient Bayesain analysis the convergence of the Markov chain Monte Carlo (MCMC) chains was explored graphically using AWTY [38]. The final posterior sample of trees is summarized as a majority rule consensus tree in Fig 1.

Bottom Line: The relationship between both traits (oncogenicity and PDZ degradation potential) is best explained by a model in which the potential to degrade PDZ proteins was acquired prior to the oncogenic phenotype.This suggests that HPV E6 directed degradation of PDZ-proteins represents an ancient ecological niche adaptation.Phylogenetic modeling indicates that this phenotype is not specifically correlated with oncogenic risk, but may act as an enabling phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.

ABSTRACT
In order to complete their life cycle, papillomaviruses have evolved to manipulate a plethora of cellular pathways. The products of the human Alphapapillomavirus E6 proteins specifically interact with and target PDZ containing proteins for degradation. This viral phenotype has been suggested to play a role in viral oncogenesis. To analyze the association of HPV E6 mediated PDZ-protein degradation with cervical oncogenesis, a high-throughput cell culture assay was developed. Degradation of an epitope tagged human MAGI1 isoform was visualized by immunoblot. The correlation between HPV E6-induced degradation of hMAGI1 and epidemiologically determined HPV oncogenicity was evaluated using a Bayesian approach within a phylogenetic context. All tested oncogenic types degraded the PDZ-containing protein hMAGI1d; however, E6 proteins isolated from several related albeit non-oncogenic viral types were equally efficient at degrading hMAGI1. The relationship between both traits (oncogenicity and PDZ degradation potential) is best explained by a model in which the potential to degrade PDZ proteins was acquired prior to the oncogenic phenotype. This analysis provides evidence that the ancestor of both oncogenic and non-oncogenic HPVs acquired the potential to degrade human PDZ-containing proteins. This suggests that HPV E6 directed degradation of PDZ-proteins represents an ancient ecological niche adaptation. Phylogenetic modeling indicates that this phenotype is not specifically correlated with oncogenic risk, but may act as an enabling phenotype. The role of PDZ protein degradation in HPV fitness and oncogenesis needs to be interpreted in the context of Alphapapillomavirus evolution.

No MeSH data available.


Related in: MedlinePlus