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Ubiquitination by SAG regulates macrophage survival/death and immune response during infection
The checkpoint between the life and death of macrophages is crucial for the host's frontline immune defense during acute phase infection. However, the mechanism as to how the immune cell equilibrates between apoptosis and immune response is unclear. Using in vitro and ex vivo approaches, we sho...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131172/ https://www.ncbi.nlm.nih.gov/pubmed/24786833 http://dx.doi.org/10.1038/cdd.2014.54 |
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author | Chang, S C Ding, J L |
author_facet | Chang, S C Ding, J L |
author_sort | Chang, S C |
collection | PubMed |
description | The checkpoint between the life and death of macrophages is crucial for the host's frontline immune defense during acute phase infection. However, the mechanism as to how the immune cell equilibrates between apoptosis and immune response is unclear. Using in vitro and ex vivo approaches, we showed that macrophage survival is synchronized by SAG (sensitive to apoptosis gene), which is a key member of the ubiquitin–proteasome system (UPS). When challenged by pathogen-associated molecular patterns (PAMPs), we observed a reciprocal expression profile of pro- and antiapoptotic factors in macrophages. However, SAG knockdown disrupted this balance. Further analysis revealed that ubiquitination of Bax and SARM (sterile α- and HEAT/armadillo-motif-containing protein) by SAG-UPS confers survival advantage to infected macrophages. SAG knockdown caused the accumulation of proapoptotic Bax and SARM, imbalance of Bcl-2/Bax in the mitochondria, induction of cytosolic cytochrome c and activation of caspase-9 and -3, all of which led to disequilibrium between life and death of macrophages. In contrast, SAG-overexpressing macrophages challenged with PAMPs exhibited upregulation of protumorigenic cytokines (IL-1β, IL-6 and TNF-α), and downregulation of antitumorigenic cytokine (IL-12p40) and anti-inflammatory cytokine (IL-10). This suggests that SAG-dependent UPS is a key switch between immune defense and apoptosis or immune overactivation and tumorigenesis. Altogether, our results indicate that SAG-UPS facilitates a timely and appropriate level of immune response, prompting future development of potential immunomodulators of SAG-UPS. |
format | Online Article Text |
id | pubmed-4131172 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-41311722014-09-01 Ubiquitination by SAG regulates macrophage survival/death and immune response during infection Chang, S C Ding, J L Cell Death Differ Original Paper The checkpoint between the life and death of macrophages is crucial for the host's frontline immune defense during acute phase infection. However, the mechanism as to how the immune cell equilibrates between apoptosis and immune response is unclear. Using in vitro and ex vivo approaches, we showed that macrophage survival is synchronized by SAG (sensitive to apoptosis gene), which is a key member of the ubiquitin–proteasome system (UPS). When challenged by pathogen-associated molecular patterns (PAMPs), we observed a reciprocal expression profile of pro- and antiapoptotic factors in macrophages. However, SAG knockdown disrupted this balance. Further analysis revealed that ubiquitination of Bax and SARM (sterile α- and HEAT/armadillo-motif-containing protein) by SAG-UPS confers survival advantage to infected macrophages. SAG knockdown caused the accumulation of proapoptotic Bax and SARM, imbalance of Bcl-2/Bax in the mitochondria, induction of cytosolic cytochrome c and activation of caspase-9 and -3, all of which led to disequilibrium between life and death of macrophages. In contrast, SAG-overexpressing macrophages challenged with PAMPs exhibited upregulation of protumorigenic cytokines (IL-1β, IL-6 and TNF-α), and downregulation of antitumorigenic cytokine (IL-12p40) and anti-inflammatory cytokine (IL-10). This suggests that SAG-dependent UPS is a key switch between immune defense and apoptosis or immune overactivation and tumorigenesis. Altogether, our results indicate that SAG-UPS facilitates a timely and appropriate level of immune response, prompting future development of potential immunomodulators of SAG-UPS. Nature Publishing Group 2014-09 2014-05-02 /pmc/articles/PMC4131172/ /pubmed/24786833 http://dx.doi.org/10.1038/cdd.2014.54 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Original Paper Chang, S C Ding, J L Ubiquitination by SAG regulates macrophage survival/death and immune response during infection |
title | Ubiquitination by SAG regulates macrophage survival/death and immune response during infection |
title_full | Ubiquitination by SAG regulates macrophage survival/death and immune response during infection |
title_fullStr | Ubiquitination by SAG regulates macrophage survival/death and immune response during infection |
title_full_unstemmed | Ubiquitination by SAG regulates macrophage survival/death and immune response during infection |
title_short | Ubiquitination by SAG regulates macrophage survival/death and immune response during infection |
title_sort | ubiquitination by sag regulates macrophage survival/death and immune response during infection |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131172/ https://www.ncbi.nlm.nih.gov/pubmed/24786833 http://dx.doi.org/10.1038/cdd.2014.54 |
work_keys_str_mv | AT changsc ubiquitinationbysagregulatesmacrophagesurvivaldeathandimmuneresponseduringinfection AT dingjl ubiquitinationbysagregulatesmacrophagesurvivaldeathandimmuneresponseduringinfection |