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Rhinovirus 3C protease suppresses apoptosis and triggers caspase-independent cell death

Apoptosis and programmed necrosis (necroptosis) determine cell fate, and antagonize infection. Execution of these complementary death pathways involves the formation of receptor-interacting protein kinase 1 (RIPK1) containing complexes. RIPK1 binds to adaptor proteins, such as TRIF (Toll-IL-1 recept...

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Autores principales: Lötzerich, Mark, Roulin, Pascal S., Boucke, Karin, Witte, Robert, Georgiev, Oleg, Greber, Urs F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833640/
https://www.ncbi.nlm.nih.gov/pubmed/29449668
http://dx.doi.org/10.1038/s41419-018-0306-6
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author Lötzerich, Mark
Roulin, Pascal S.
Boucke, Karin
Witte, Robert
Georgiev, Oleg
Greber, Urs F.
author_facet Lötzerich, Mark
Roulin, Pascal S.
Boucke, Karin
Witte, Robert
Georgiev, Oleg
Greber, Urs F.
author_sort Lötzerich, Mark
collection PubMed
description Apoptosis and programmed necrosis (necroptosis) determine cell fate, and antagonize infection. Execution of these complementary death pathways involves the formation of receptor-interacting protein kinase 1 (RIPK1) containing complexes. RIPK1 binds to adaptor proteins, such as TRIF (Toll-IL-1 receptor-domain-containing-adaptor-inducing interferon-beta factor), FADD (Fas-associated-protein with death domain), NEMO (NF-κB regulatory subunit IKKγ), SQSTM1 (sequestosome 1/p62), or RIPK3 (receptor-interacting protein kinase 3), which are involved in RNA sensing, NF-κB signaling, autophagosome formation, apoptosis, and necroptosis. We report that a range of rhinoviruses impair apoptosis and necroptosis in epithelial cells late in infection. Unlike the double-strand (ds) RNA mimetic poly I:C (polyinosinic:polycytidylic acid), the exposure of dsRNA to toll-like receptor 3 (TLR3) in rhinovirus-infected cells did not lead to apoptosis execution. Accordingly, necroptosis and the production of ROS (reactive oxygen species) were not observed late in infection, when RIPK3 was absent. Instead, a virus-induced alternative necrotic cell death pathway proceeded, which led to membrane rupture, indicated by propidium iodide staining. The impairment of dsRNA-induced apoptosis late in infection was controlled by the viral 3C-protease (3Cpro), which disrupted RIPK1-TRIF/FADD /SQSTM1 immune-complexes. 3Cpro and 3C precursors were found to coimmuno-precipitate with RIPK1, cleaving the RIPK1 death-domain, and generating N-terminal RIPK1 fragments. The depletion of RIPK1 or chemical inhibition of its kinase at the N-terminus did not interfere with virus progeny formation or cell fate. The data show that rhinoviruses suppress apoptosis and necroptosis, and release progeny by an alternative cell death pathway, which is controlled by viral proteases modifying innate immune complexes.
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spelling pubmed-58336402018-03-06 Rhinovirus 3C protease suppresses apoptosis and triggers caspase-independent cell death Lötzerich, Mark Roulin, Pascal S. Boucke, Karin Witte, Robert Georgiev, Oleg Greber, Urs F. Cell Death Dis Article Apoptosis and programmed necrosis (necroptosis) determine cell fate, and antagonize infection. Execution of these complementary death pathways involves the formation of receptor-interacting protein kinase 1 (RIPK1) containing complexes. RIPK1 binds to adaptor proteins, such as TRIF (Toll-IL-1 receptor-domain-containing-adaptor-inducing interferon-beta factor), FADD (Fas-associated-protein with death domain), NEMO (NF-κB regulatory subunit IKKγ), SQSTM1 (sequestosome 1/p62), or RIPK3 (receptor-interacting protein kinase 3), which are involved in RNA sensing, NF-κB signaling, autophagosome formation, apoptosis, and necroptosis. We report that a range of rhinoviruses impair apoptosis and necroptosis in epithelial cells late in infection. Unlike the double-strand (ds) RNA mimetic poly I:C (polyinosinic:polycytidylic acid), the exposure of dsRNA to toll-like receptor 3 (TLR3) in rhinovirus-infected cells did not lead to apoptosis execution. Accordingly, necroptosis and the production of ROS (reactive oxygen species) were not observed late in infection, when RIPK3 was absent. Instead, a virus-induced alternative necrotic cell death pathway proceeded, which led to membrane rupture, indicated by propidium iodide staining. The impairment of dsRNA-induced apoptosis late in infection was controlled by the viral 3C-protease (3Cpro), which disrupted RIPK1-TRIF/FADD /SQSTM1 immune-complexes. 3Cpro and 3C precursors were found to coimmuno-precipitate with RIPK1, cleaving the RIPK1 death-domain, and generating N-terminal RIPK1 fragments. The depletion of RIPK1 or chemical inhibition of its kinase at the N-terminus did not interfere with virus progeny formation or cell fate. The data show that rhinoviruses suppress apoptosis and necroptosis, and release progeny by an alternative cell death pathway, which is controlled by viral proteases modifying innate immune complexes. Nature Publishing Group UK 2018-02-15 /pmc/articles/PMC5833640/ /pubmed/29449668 http://dx.doi.org/10.1038/s41419-018-0306-6 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lötzerich, Mark
Roulin, Pascal S.
Boucke, Karin
Witte, Robert
Georgiev, Oleg
Greber, Urs F.
Rhinovirus 3C protease suppresses apoptosis and triggers caspase-independent cell death
title Rhinovirus 3C protease suppresses apoptosis and triggers caspase-independent cell death
title_full Rhinovirus 3C protease suppresses apoptosis and triggers caspase-independent cell death
title_fullStr Rhinovirus 3C protease suppresses apoptosis and triggers caspase-independent cell death
title_full_unstemmed Rhinovirus 3C protease suppresses apoptosis and triggers caspase-independent cell death
title_short Rhinovirus 3C protease suppresses apoptosis and triggers caspase-independent cell death
title_sort rhinovirus 3c protease suppresses apoptosis and triggers caspase-independent cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833640/
https://www.ncbi.nlm.nih.gov/pubmed/29449668
http://dx.doi.org/10.1038/s41419-018-0306-6
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