Schneider-Brachert, Wulf and Tchikov, Vladimir and Merkel, Oliver and Jakob, Marten and Hallas, Cora and Kruse, Marie-Luise and Groitl, Peter and Lehn, Alexander and Hildt, Eberhard and Held-Feindt, Janka and Dobner, Thomas and Kabelitz, Dieter and Kroenke, Martin and Schuetze, Stefan (2006) Inhibition of TNF receptor 1 internalization by adenovirus 14.7K as a novel immune escape mechanism. JOURNAL OF CLINICAL INVESTIGATION, 116 (11). pp. 2901-2913. ISSN 0021-9738,
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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 figand-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-kappa B 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR-NECROSIS-FACTOR; E3 14.7-KILODALTON PROTEIN; ALPHA-INDUCED APOPTOSIS; INFLAMMATORY RESPONSES; MEDIATED APOPTOSIS; ENDOCYTIC PATHWAY; FACTOR CYTOLYSIS; CELL-DEATH; E1B 19K; COMPLEX; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Jan 2021 11:43 |
| Last Modified: | 19 Jan 2021 11:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/33810 |
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