Inhibition of TNF receptor 1 internalization by adenovirus 14.7K as a novel immune escape mechanism
Wulf Schneider-Brachert, … , Martin Krönke, Stefan Schütze
Wulf Schneider-Brachert, … , Martin Krönke, Stefan Schütze
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):2901-2913. https://doi.org/10.1172/JCI23771.
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Research Article Virology

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

Abstract

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-κB 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.

Authors

Wulf Schneider-Brachert, Vladimir Tchikov, Oliver Merkel, Marten Jakob, Cora Hallas, Marie-Luise Kruse, Peter Groitl, Alexander Lehn, Eberhard Hildt, Janka Held-Feindt, Thomas Dobner, Dieter Kabelitz, Martin Krönke, Stefan Schütze

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Figure 7

14.7K inhibits TNFR1 internalization in H1299 cells.

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14.7K inhibits TNFR1 internalization in H1299 cells. Cells were labeled ...
Cells were labeled with biotin-TNF/streptavidin-FITC complexes at 4°C for 45 minutes (A–C), and TNFR1 endocytosis was monitored after a temperature shift to 37°C for 45–240 minutes by confocal laser microscopy (D–L). (A–C) Labeled TNFR1 complexes were detected after 45 minutes at 4°C strictly on the surface of all cells. After incubation at 37°C for the indicated time points, only in H1299 parental (D, G, and J) and H1299 vector cells (E, H, and K) was TNFR1 endocytosis detected, whereas in 14.7K H1299 cells (F, I, and L), receptor complexes remained on the cell surface, indicating inhibited internalization of TNFR1.