An indirect immunofluorescence image using a mouse monoclonal antibody specific for TRAIL receptor 1. Courtesy of Ann Tollefson, St. Louis University, USA.

As any housing officer will tell you, squatters (people who take unauthorized possession of unoccupied premises) use many tricks to avoid detection and eviction. Viruses use similarly cunning mechanisms to ensure that the cells they reside in are not targeted for destruction, via apoptosis, by the immune system. Tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, is emerging as an important molecule used by cells of the immune system to kill virus-infected cells, but how, or if, viruses can inhibit TRAIL-induced apoptosis is unknown. Tollefson and colleagues now report, in the Journal of Virology, that adenoviruses have evolved proteins that inhibit TRAIL-induced apoptosis, so enabling persistance of the viral infection.

Previous studies have established that proteins encoded by the E1B and E3 transcription units of adenovirus, including E1B-19K, E3-14.7K and the E3 protein RID (receptor internalization and degradation), protect infected cells from apoptosis induced by TNF-α and Fas ligand (FasL). In the present study, the authors carried out apoptosis assays on A549 human lung carcinoma cells infected with wild-type adenovirus or with mutants that lack one or more E3 or E1B protein in the presence of TRAIL and cycloheximide (which increases the sensitivity of cells to TRAIL-induced apoptosis). Mock-infected cells underwent apoptosis, as did cells infected with mutants that lacked the expression of RID, E3-14.7K and E1B-19K. However, cells infected with wild-type adenovirus or mutants expressing RID, but not E1B-19K or E3-14.7K, remained viable. Therefore, the adenoviral protein RID can block TRAIL-induced apoptosis.

How does RID inhibit the TRAIL pathway? The authors have previously shown that RID proteins protect against Fas-induced apoptosis by causing internalization and degradation of cell-surface Fas. Here, they show that the same applies for TRAIL; TRAIL-receptor 1 is cleared from the surface of cells infected by wild-type adenovirus, or any mutant expressing RID, and is transported to lysosomes for degradation. This study therefore provides an insight into how adenoviruses inactivate TRAIL-induced apoptotic pathways and so avoid eviction.