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.

在白介素1（IL-1）细胞因子家族中，IL-1受体辅助蛋白（IL-1RAcP）是八种受体-细胞因子对的共受体，包括那些涉及细胞因子IL-1β和IL-33的受体。与IL-1β不同，IL-33没有包含其同源受体ST2和共享的共受体IL-1RAcP的信号传导复合物，我们现在在此进行介绍。尽管IL-1β和IL-33复合物具有相同的结构特征并与IL-1RAcP的分子表面结合，但这些细胞因子对于共受体结合和信号激活具有截然不同的策略。我们的数据表明，IL-1β与IL-1RI结合以正确地将细胞因子呈递给IL-1RAcP，而IL-33与ST2结合，以构象地限制同源受体处于IL-1RAcP接受状态。