| Adenovirus type 5 rupture of lysosomes leads to cathepsin B-dependent mitochondrial stress and production of reactive oxygen species. | |
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MedLine Citation:
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PMID: 21835790 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In response to viral infection, reactive oxygen species (ROS) mediate innate immune signaling or generate danger signals to activate immune cells. The mechanisms of virally induced ROS are poorly defined, however. We demonstrate that ROS are produced within minutes of adenovirus type 5 (Ad5) infection of macrophages and that oxidative stress supports Ad5-induced cytokine secretion. We show that short hairpin RNA (shRNA) knockdown of TLR9 has no effect on ROS production despite observed decreases in Ad-induced cytokine secretion. A major source of ROS in macrophages is NADPH oxidase. However, shRNA knockdown of the NADPH oxidase subunit NOX2 does not attenuate Ad-induced ROS. Induction of ROS is not observed in cells infected with a temperature-sensitive mutant of Ad2, ts1, which is defective in endosomal membrane penetration during cell entry. Further, Ad5, but not ts1, induces the release of lysosomal cathepsin B into the cytoplasm of infected cells. In agreement with this finding, we observe a loss of mitochondrial membrane potential upon Ad infection which requires Ad endosomal membrane penetration and cathepsin B activity. Overexpression of Bcl-2 attenuates Ad5-induced ROS, further supporting the role for mitochondrial membrane destabilization as the source of ROS in response to Ad5 infection. Together, these data suggest that ROS produced in response to Ad5 infection depends on the virally induced endosomal membrane rupture to release lysosomal cathepsins. Furthermore, the release of cathepsins leads to mitochondrial membrane disruption and thus the release of ROS from the mitochondria. |
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Authors:
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Kathleen A McGuire; Arlene U Barlan; Tina M Griffin; Christopher M Wiethoff |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-08-10 |
Journal Detail:
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Title: Journal of virology Volume: 85 ISSN: 1098-5514 ISO Abbreviation: J. Virol. Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-09-22 Completed Date: 2011-11-07 Revised Date: 2012-04-02 |
Medline Journal Info:
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Nlm Unique ID: 0113724 Medline TA: J Virol Country: United States |
Other Details:
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Languages: eng Pagination: 10806-13 Citation Subset: IM |
Affiliation:
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Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Avenue, Maywood, IL 60153, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenoviridae
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immunology* Cathepsin B / metabolism* Cell Line Cytokines / secretion Humans Lysosomes / enzymology*, virology* Macrophages / immunology, virology Membrane Potential, Mitochondrial Mitochondria / metabolism* Mitochondrial Membranes / physiology Reactive Oxygen Species / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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AI007508/AI/NIAID NIH HHS; AI082430/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Reactive Oxygen Species; EC 3.4.22.1/Cathepsin B |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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