Interferons induce proteolytic degradation of TRAILR4.
IFNgamma and its transcriptional target tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) are two major effector molecules of activated CTLs and NK cells. Here, we show that IFNgamma as well as the type I interferon IFNalpha strongly inhibit cell surface expression of the decoy receptor TRAILR4 while having only a moderate inhibitory or even an inducing effect on TRAILR2 and CD95. Interferon-induced inhibition of TRAILR4 expression was blocked by a protease inhibitor cocktail and also by MG132, suggesting that down-regulation of TRAILR4 involves the proteasome. Inhibition of TRAILR4 expression by siRNA sensitized for TRAIL-, but not CD95L-induced apoptosis. Thus, the apoptosis-inducing action of interferons may not only rely on the well-established induction of TRAIL in effector cells but also on concomitant down-regulation of its antagonizing decoy receptor TRAILR4 in target cells.
Wicovsky
Andreas
A
Department of Molecular Internal Medicine, Medical Polyclinic, University of Würzburg, Röntgenring 11, 97070 Wurzburg, Germany.
Siegmund
Daniela
D
Wajant
Harald
H
D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*
D016898:Interferon-alpha; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; D007371:Interferon-gamma