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Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex

The hepatitis B virus (HBV) regulatory HBx protein is required for infection, and its binding to cellular damaged DNA binding protein 1 (DDB1) is critical for this function. DDB1 is an adaptor protein for the cullin 4A Really Interesting New Gene (RING) E3 ubiquitin ligase (CRL4) complex and functio...

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Autores principales: Minor, Marissa M., Hollinger, F. Blaine, McNees, Adrienne L., Jung, Sung Yun, Jain, Antrix, Hyser, Joseph M., Bissig, Karl-Dimiter, Slagle, Betty L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226812/
https://www.ncbi.nlm.nih.gov/pubmed/32235678
http://dx.doi.org/10.3390/cells9040834
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author Minor, Marissa M.
Hollinger, F. Blaine
McNees, Adrienne L.
Jung, Sung Yun
Jain, Antrix
Hyser, Joseph M.
Bissig, Karl-Dimiter
Slagle, Betty L.
author_facet Minor, Marissa M.
Hollinger, F. Blaine
McNees, Adrienne L.
Jung, Sung Yun
Jain, Antrix
Hyser, Joseph M.
Bissig, Karl-Dimiter
Slagle, Betty L.
author_sort Minor, Marissa M.
collection PubMed
description The hepatitis B virus (HBV) regulatory HBx protein is required for infection, and its binding to cellular damaged DNA binding protein 1 (DDB1) is critical for this function. DDB1 is an adaptor protein for the cullin 4A Really Interesting New Gene (RING) E3 ubiquitin ligase (CRL4) complex and functions by binding cellular DDB1 cullin associated factor (DCAF) receptor proteins that recruit substrates for ubiquitination and degradation. We compared the proteins found in the CRL4 complex immunoprecipitated from uninfected versus HBV-infected hepatocytes from human liver chimeric mice for insight into mechanisms by which HBV and the cell interact within the CRL4 complex. Consistent with its role as a viral DCAF, HBx was found in the HBV CRL4 complexes. In tissue culture transfection experiments, we showed that HBx expression led to decreased levels of known restriction factor structural maintenance of chromosomes protein 6 (SMC6) and putative restriction factors stromal interaction molecule 1 (STIM1, zinc finger E-box binding homeobox 2 (ZEB2), and proteasome activator subunit 4 (PSME4). Moreover, silencing of these proteins led to increased HBV replication in the HepG2-sodium taurocholate cotransporting polypeptide (NTCP) infection model. We also identified cellular DCAF receptors in CRL4 complexes from humanized mice. Increasing amounts of HBx did not reveal competitive DCAF binding to cullin4 (CUL4)-DDB1 in plasmid-transfected cells. Our results suggest a model in which HBx benefits virus replication by directly or indirectly degrading multiple cellular restriction factors.
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spelling pubmed-72268122020-05-18 Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex Minor, Marissa M. Hollinger, F. Blaine McNees, Adrienne L. Jung, Sung Yun Jain, Antrix Hyser, Joseph M. Bissig, Karl-Dimiter Slagle, Betty L. Cells Article The hepatitis B virus (HBV) regulatory HBx protein is required for infection, and its binding to cellular damaged DNA binding protein 1 (DDB1) is critical for this function. DDB1 is an adaptor protein for the cullin 4A Really Interesting New Gene (RING) E3 ubiquitin ligase (CRL4) complex and functions by binding cellular DDB1 cullin associated factor (DCAF) receptor proteins that recruit substrates for ubiquitination and degradation. We compared the proteins found in the CRL4 complex immunoprecipitated from uninfected versus HBV-infected hepatocytes from human liver chimeric mice for insight into mechanisms by which HBV and the cell interact within the CRL4 complex. Consistent with its role as a viral DCAF, HBx was found in the HBV CRL4 complexes. In tissue culture transfection experiments, we showed that HBx expression led to decreased levels of known restriction factor structural maintenance of chromosomes protein 6 (SMC6) and putative restriction factors stromal interaction molecule 1 (STIM1, zinc finger E-box binding homeobox 2 (ZEB2), and proteasome activator subunit 4 (PSME4). Moreover, silencing of these proteins led to increased HBV replication in the HepG2-sodium taurocholate cotransporting polypeptide (NTCP) infection model. We also identified cellular DCAF receptors in CRL4 complexes from humanized mice. Increasing amounts of HBx did not reveal competitive DCAF binding to cullin4 (CUL4)-DDB1 in plasmid-transfected cells. Our results suggest a model in which HBx benefits virus replication by directly or indirectly degrading multiple cellular restriction factors. MDPI 2020-03-30 /pmc/articles/PMC7226812/ /pubmed/32235678 http://dx.doi.org/10.3390/cells9040834 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
Minor, Marissa M.
Hollinger, F. Blaine
McNees, Adrienne L.
Jung, Sung Yun
Jain, Antrix
Hyser, Joseph M.
Bissig, Karl-Dimiter
Slagle, Betty L.
Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex
title Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex
title_full Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex
title_fullStr Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex
title_full_unstemmed Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex
title_short Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex
title_sort hepatitis b virus hbx protein mediates the degradation of host restriction factors through the cullin 4 ddb1 e3 ubiquitin ligase complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226812/
https://www.ncbi.nlm.nih.gov/pubmed/32235678
http://dx.doi.org/10.3390/cells9040834
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