IL-1 Family Cytokines Use Distinct Molecular Mechanisms to Signal through Their Shared Co-receptor

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Sebastian Günther, Daniel Deredge, Amanda L. Bowers, Alessandra Luchini, Daniel A. Bonsor, Robert Beadenkopf, Lance Liotta, Patrick L. Wintrode, Eric J. Sundberg
Within the interleukin 1 (IL-1) cytokine family, IL-1 receptor accessory protein (IL-1RAcP) is the co-receptor for eight receptor-cytokine pairs, including those involving cytokines IL-1β and IL-33. Unlike IL-1β, IL-33 does not have a signaling complex that includes both its cognate receptor, ST2, and the shared co-receptor IL-1RAcP, which we now present here. Although the IL-1β and IL-33 complexes shared structural features and engaged identical molecular surfaces of IL-1RAcP, these cytokines had starkly different strategies for co-receptor engagement and signal activation. Our data suggest that IL-1β binds to IL-1RI to properly present the cytokine to IL-1RAcP, whereas IL-33 binds to ST2 in order to conformationally constrain the cognate receptor in an IL-1RAcP-receptive state. These findings indicate that members of the IL-1 family of cytokines use distinct molecular mechanisms to signal through their shared co-receptor, and they provide the foundation from which to design new therapies to target IL-33 signaling.

Graphical abstract

Teaser

IL-1RAcP is the co-receptor shared by most cytokines in the IL-1 family. Günther et al. demonstrate that although IL-1RAcP interacts with different cytokine-receptor pairs through a conserved architecture, it uses starkly different strategies to engage IL-1β and IL-33 and form signaling-competent ternary complexes.


http://ift.tt/2xn9zRA