Inhibition of TNF receptor 1 internalization by adenovirus 14.7K as a novel immune escape mechanism

The adenoviral protein E3-14.7K (14.7K) is an inhibitor of TNF-induced apoptosis, but the molecular mechanism underlying this protective effect has not yet been explained exhaustively. TNF-mediated apoptosis is initiated by ligand-induced recruitment of TNF receptor-associated death domain (TRADD),...

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Bibliographic Details
Published in:The Journal of clinical investigation 2006-11, Vol.116 (11), p.2901-2913
Main Authors: Schneider-Brachert, Wulf, Tchikov, Vladimir, Merkel, Oliver, Jakob, Marten, Hallas, Cora, Kruse, Marie-Luise, Groitl, Peter, Lehn, Alexander, Hildt, Eberhard, Held-Feindt, Janka, Dobner, Thomas, Kabelitz, Dieter, Krönke, Martin, Schütze, Stefan
Format: Article
Language:English
Subjects:
Adenoviridae - immunology
Adenovirus E3 Proteins - genetics
Adenovirus E3 Proteins - immunology
Adenovirus E3 Proteins - metabolism
Adenoviruses
Analysis
Animals
Apoptosis
Biomedical research
Cell Line
Cells
Cytotoxicity
Death Domain Receptor Signaling Adaptor Proteins - metabolism
Defense mechanisms
Endocytosis
Humans
Ligands
Mice
NF-kappa B - metabolism
Proteins
Receptors, Tumor Necrosis Factor - antagonists & inhibitors
Receptors, Tumor Necrosis Factor - immunology
Receptors, Tumor Necrosis Factor - metabolism
Recruitment
Tumor necrosis factor
Tumor Necrosis Factor-alpha - metabolism
Virus Internalization
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Summary:The adenoviral protein E3-14.7K (14.7K) is an inhibitor of TNF-induced apoptosis, but the molecular mechanism underlying this protective effect has not yet been explained exhaustively. TNF-mediated apoptosis is initiated by ligand-induced recruitment of TNF receptor-associated death domain (TRADD), Fas-associated death domain (FADD), and caspase-8 to the death domain of TNF receptor 1 (TNFR1), thereby establishing the death-inducing signaling complex (DISC). Here we report that adenovirus 14.7K protein inhibits ligand-induced TNFR1 internalization. Analysis of purified magnetically labeled TNFR1 complexes from murine and human cells stably transduced with 14.7K revealed that prevention of TNFR1 internalization resulted in inhibition of DISC formation. In contrast, 14.7K did not affect TNF-induced NF-kappaB activation via recruitment of receptor-interacting protein 1 (RIP-1) and TNF receptor-associated factor 2 (TRAF-2). Inhibition of endocytosis by 14.7K was effected by failure of coordinated temporal and spatial assembly of essential components of the endocytic machinery such as Rab5 and dynamin 2 at the site of the activated TNFR1. Furthermore, we found that the same TNF defense mechanisms were instrumental in protecting wild-type adenovirus-infected human cells expressing 14.7K. This study describes a new molecular mechanism implemented by a virus to escape immunosurveillance by selectively targeting TNFR1 endocytosis to prevent TNF-induced DISC formation.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci23771