title: 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-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.
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
authors.forename: Wulf
authors.initials: W
authors.lastname: Schneider-Brachert
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tchikov
authors.forename: Oliver
authors.initials: O
authors.lastname: Merkel
authors.forename: Marten
authors.initials: M
authors.lastname: Jakob
authors.forename: Cora
authors.initials: C
authors.lastname: Hallas
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Kruse
authors.forename: Peter
authors.initials: P
authors.lastname: Groitl
authors.forename: Alexander
authors.initials: A
authors.lastname: Lehn
authors.forename: Eberhard
authors.initials: E
authors.lastname: Hildt
authors.forename: Janka
authors.initials: J
authors.lastname: Held-Feindt
authors.forename: Thomas
authors.initials: T
authors.lastname: Dobner
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.forename: Stefan
authors.initials: S
authors.lastname: Schütze
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D017503:Adenovirus E3 Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D017503:Adenovirus E3 Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; C509184:E3 14.7K protein, Adenovirus; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha