Inhibition of TNF receptor 1 internalization by adenovirus 14.7K as a novel immune escape mechanism
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
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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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 11

The DISC is absent in H1299 cells infected with wild-type Ad5.

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The DISC is absent in H1299 cells infected with wild-type Ad5. Magnetic ...
Magnetic TNFR1 fractions were prepared from infected H1299 cells and immunoblotted with the indicated antibodies. In H1299 cells infected with the mutant Ad5 19K–/E3– and Ad5 19K–/PM-14.7K, the DISC proteins TRADD, FADD, activated caspase-8, as well as RIP-1 and TRAF-2 were recruited to TNFR1 after 30 minutes. In contrast, in wild-type Ad5–infected cells, establishment of the DISC was nearly abolished, but RIP-1 and TRAF-2 were still detected. Furthermore, TNF-induced recruitment of the endocytic adaptor proteins Rab5 and dynamin 2 was clearly visible in cells infected with either mutant virus but nearly abolished in cells infected with wild-type virus.