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Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase

Enteroviruses (EVs) usurp the host autophagy pathway for pro-viral functions; however, the consequence of EV-induced diversion of autophagy on organelle quality control is poorly defined. Using coxsackievirus B3 (CVB3) as a model EV, we explored the interplay between EV infection and selective autop...

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Autores principales: Mohamud, Yasir, Xue, Yuan Chao, Liu, Huitao, Ng, Chen Seng, Bahreyni, Amirhossein, Luo, Honglin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213198/
https://www.ncbi.nlm.nih.gov/pubmed/34149637
http://dx.doi.org/10.3389/fmicb.2021.647410
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author Mohamud, Yasir
Xue, Yuan Chao
Liu, Huitao
Ng, Chen Seng
Bahreyni, Amirhossein
Luo, Honglin
author_facet Mohamud, Yasir
Xue, Yuan Chao
Liu, Huitao
Ng, Chen Seng
Bahreyni, Amirhossein
Luo, Honglin
author_sort Mohamud, Yasir
collection PubMed
description Enteroviruses (EVs) usurp the host autophagy pathway for pro-viral functions; however, the consequence of EV-induced diversion of autophagy on organelle quality control is poorly defined. Using coxsackievirus B3 (CVB3) as a model EV, we explored the interplay between EV infection and selective autophagy receptors, i.e., Tax1-binding protein 1/TRAF6-binding protein (T6BP), optineurin (OPTN), and nuclear dot 10 protein 52 (NDP52), known to be involved in regulating the clearance of damaged mitochondria, a process termed as mitophagy. Following CVB3 infection, we showed significant perturbations of the mitochondrial network coincident with degradation of the autophagy receptor protein T6BP, similar phenomenon to what we previously observed on NDP52. Notably, protein levels of OPTN are not altered during early infection and slightly reduced upon late infection. Cell culture studies revealed that T6BP degradation occurs independent of the function of host caspases and viral proteinase 3C, but requires the proteolytic activity of viral proteinase 2A. Further investigation identified the cleavage site on T6BP after the amino acid 621 that separates the C-terminal ubiquitin-binding domain from the other functional domains at the N-terminus. Genetic silencing of T6BP and OPTN results in the attenuation of CVB3 replication, suggesting a pro-viral activity for these two proteins. Finally, functional assessment of cleaved fragments from NDP52 and T6BP revealed abnormal binding affinity and impaired capacity to be recruited to depolarized mitochondria. Collectively, these results suggest that CVB3 targets autophagy receptors to impair selective autophagy.
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spelling pubmed-82131982021-06-19 Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase Mohamud, Yasir Xue, Yuan Chao Liu, Huitao Ng, Chen Seng Bahreyni, Amirhossein Luo, Honglin Front Microbiol Microbiology Enteroviruses (EVs) usurp the host autophagy pathway for pro-viral functions; however, the consequence of EV-induced diversion of autophagy on organelle quality control is poorly defined. Using coxsackievirus B3 (CVB3) as a model EV, we explored the interplay between EV infection and selective autophagy receptors, i.e., Tax1-binding protein 1/TRAF6-binding protein (T6BP), optineurin (OPTN), and nuclear dot 10 protein 52 (NDP52), known to be involved in regulating the clearance of damaged mitochondria, a process termed as mitophagy. Following CVB3 infection, we showed significant perturbations of the mitochondrial network coincident with degradation of the autophagy receptor protein T6BP, similar phenomenon to what we previously observed on NDP52. Notably, protein levels of OPTN are not altered during early infection and slightly reduced upon late infection. Cell culture studies revealed that T6BP degradation occurs independent of the function of host caspases and viral proteinase 3C, but requires the proteolytic activity of viral proteinase 2A. Further investigation identified the cleavage site on T6BP after the amino acid 621 that separates the C-terminal ubiquitin-binding domain from the other functional domains at the N-terminus. Genetic silencing of T6BP and OPTN results in the attenuation of CVB3 replication, suggesting a pro-viral activity for these two proteins. Finally, functional assessment of cleaved fragments from NDP52 and T6BP revealed abnormal binding affinity and impaired capacity to be recruited to depolarized mitochondria. Collectively, these results suggest that CVB3 targets autophagy receptors to impair selective autophagy. Frontiers Media S.A. 2021-06-04 /pmc/articles/PMC8213198/ /pubmed/34149637 http://dx.doi.org/10.3389/fmicb.2021.647410 Text en Copyright © 2021 Mohamud, Xue, Liu, Ng, Bahreyni and Luo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Mohamud, Yasir
Xue, Yuan Chao
Liu, Huitao
Ng, Chen Seng
Bahreyni, Amirhossein
Luo, Honglin
Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase
title Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase
title_full Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase
title_fullStr Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase
title_full_unstemmed Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase
title_short Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase
title_sort autophagy receptor protein tax1-binding protein 1/traf6-binding protein is a cellular substrate of enteroviral proteinase
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213198/
https://www.ncbi.nlm.nih.gov/pubmed/34149637
http://dx.doi.org/10.3389/fmicb.2021.647410
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