Comparable potency of IFN{alpha}2 and IFN{beta} on immediate JAK/STAT activation but differential down-regulation of IFNAR2

Zrinka Marijanovic (1) , Josiane Ragimbeau (1) , José van Der Heyden (2) , Gilles Uzé (2) , Sandra Pellegrini (1)

1 Signalisation des Cytokines
2 DAA - Défenses antivirales et antitumorales

Type I interferons (IFNα/β) form a family of related cytokines that control a variety of cellular functions through binding to a receptor composed of IFNAR1 and IFNAR2. Among type I IFN, the α2 and β subtypes exhibit a large difference in their binding affinities to IFNAR1 and it was suggested that high concentration of IFNAR1 may compensate for its low intrinsic binding affinity to IFNα2. We tested whether receptor-proximal signaling events are sensitive to IFNAR1 surface concentration by investigating the relationship between relative IFNAR1/IFNAR2 surface levels and IFNα2 vs IFNβ signaling potencies in several cell lines. For this, we monitored the activation profile of Jak/Stat proteins, measured basal and ligand-induced surface decay of each receptor subunit and tested the effect of variable IFNAR1 levels on IFNα2 signaling potency. Our data show that the cell surface IFNAR1 level is indeed a limiting factor for assembly of the functional complex, but an increased concentration of it does not translate into an IFNα/β differential Jak/Stat signaling nor it changes the dynamics of the engaged receptor. Importantly, however, our data highlight a differential effect upon routing of IFNAR2. Following binding of IFNα2, IFNAR2 is internalized but, instead of being routed towards degradation as it is when complexed to IFNβ, it recycles back to the cell surface. These observations strongly suggest that stability and intracellular lifetime of the ternary complex account for the differential control of IFNAR2. Moreover, this work opens up the attractive possibility that endosomal-initiated signaling may contribute to IFNα/β differential bioactivities.

Mots clés: Life Sciences

Domaines: Immunologie

Zrinka Marijanovic, Josiane Ragimbeau, José van Der Heyden, Gilles Uzé, Sandra Pellegrini. Comparable potency of IFN{alpha}2 and IFN{beta} on immediate JAK/STAT activation but differential down-regulation of IFNAR2. Biochemical Journal, 2007, 407 (1), pp.141-151. ⟨10.1042/BJ20070605⟩. ⟨hal-00478796⟩