Inhibition of TRAIL-Induced Apoptosis and Forced Internalization of TRAIL Receptor 1 by Adenovirus Proteins

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis through two receptors, TRAIL-R1 (also known as death receptor 4) and TRAIL-R2 (also known as death receptor 5), that are members of the TNF receptor superfamily of death domain-containing receptors. We show that human adenovirus type 5 encodes three proteins, named RID (previously named E3-10.4K/14.5K), E3-14.7K, and E1B-19K, that independently inhibit TRAIL-induced apoptosis of infected human cells. This conclusion was derived from studies using wild-type adenovirus, adenovirus replication-competent mutants that lack one or more of the RID, E3-14.7K, and E1B-19K genes, and adenovirus E1-minus replication-defective vectors that express all E3 genes, RID plus E3-14.7K only, RID only, or E3-14.7K only. RID inhibits TRAIL-induced apoptosis when cells are sensitized to TRAIL either by adenovirus infection or treatment with cycloheximide. RID induces the internalization of TRAIL-R1 from the cell surface, as shown by flow cytometry and indirect immunofluorescence for TRAIL-R1. TRAIL-R1 was internalized in distinct vesicles which are very likely to be endosomes and lysosomes. TRAIL-R1 is degraded, as indicated by the disappearance of the TRAIL-R1 immunofluorescence signal. Degradation was inhibited by bafilomycin A1, a drug that prevents acidification of vesicles and the sorting of receptors from late endosomes to lysosomes, implying that degradation occurs in lysosomes. RID was also shown previously to internalize and degrade another death domain receptor, Fas, and to prevent apoptosis through Fas and the TNF receptor. RID was shown previously to force the internalization and degradation of the epidermal growth factor receptor. E1B-19K was shown previously to block apoptosis through Fas, and both E1B-19K and E3-14.7K were found to prevent apoptosis through the TNF receptor. These findings suggest that the receptors for TRAIL, Fas ligand, and TNF play a role in limiting virus infections. The ability of adenovirus to inhibit killing through these receptors may prolong acute and persistent infections.

Anticancer activity of oncolytic adenovirus vector armed with IFN-α and ADP is enhanced by pharmacologically controlled expression of TRAIL

“…[45][46][47] The retention of these genes in TetON-TRAIL might be necessary for combining this vector with RC Ad in cancer cells that are highly sensitive to TRAIL-mediated apoptosis to prevent early death of the infected cells and to allow for a completion of the RC Ad infection cycle. Alternatively, the use of a weak promoter instead of an inducible promoter system for driving TRAIL expression might be sufficient for improvement of the oncolytic activity of an RC Ad in TRAIL-sensitive tumor cells.…”

Protéines Nef du VIH et K3/K5 du virus associé au sarcoma de Kaposi : des « parasites »de la voie d’endocytose

“…Les exemples de virus qui ont développé des systèmes d'induction d'internalisation de protéines membranaires sont plutôt rares. L'adénovirus humain constitue cependant un autre exemple de modulation de l'expression de récepteurs impliqués dans l'apoptose tels que Fas ou le récepteur de TRAIL [33,34]. Cette modulation passe aussi par l'expression de deux protéines virales appelées RID (receptor internalization and degradation) α et β (ou protéines E3 10.4K et 14.5K) qui avaient été initialement décrites pour induire l'internalisation du récepteur de l'EGF [35].…”

“…Il est toutefois intéressant de noter que des similitudes existent entre ces deux systèmes, puisque RID α et β sont également localisées au niveau du réticulum endoplasmique. De plus, l'expression des protéines RID à la membrane plasmique n'est observée que lorsque α et β sont co-exprimées [34], ce qui pourrait être aussi le cas pour K3 et K5.…”

Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver

“…However, genes encoded in the adenoviral E3 region prevent T-cell recognition and block TNF-mediated killing of infected cells. [32][33][34][35][36] Injection of mice with adenoviral vectors with deletions of the E3 region permitted immune recognition of infected cells but limited the expression of transgenes and increased immunemediated hepatoxicity. 37 Hepatic toxicities resulting from exposure to adenovirus can have different times of onset, degree of hepatic damage and duration depending on the mechanism causing the toxicity.…”