The helminth-derived effector protein HpBARI trimerises to selectively target membrane bound ST2 receptor

Abstract

The ST2 receptor is activated by the alarmin cytokine IL-33, inducing and controlling immune responses. ST2-mediated signalling contributes to protection from parasitic infection, but is also involved in asthma, inflammatory bowel disease, fibrosis and allergic inflammation, making inhibitors of ST2 desirable. While signalling is mediated by membrane-associated ST2 on immune cells, extracellular fluids also contain a soluble form of ST2 which acts as a decoy, soaking up IL-33. An effective ST2-targeting therapeutic will selectively target membrane-associated ST2. The intestinal helminth H. polygyrus bakeri suppresses ST2-mediated signalling to reduce helminth clearance from the gut, with the effector HpBARI2 directly binding to and inhibiting ST2. Here, we present the structure of the ST2:HpBARI2 complex. HpBARI2 forms a stable, planar trimeric structure, with three vertices each binding a single ST2. HpBARI2 occludes the IL-33 binding site of ST2 and constraints the receptor in a conformation incompatible with recruitment of signalling co-receptor IL-1RAcP. The trimeric valency of HpBARI2 results in preferential binding to multiple membrane-associated ST2 molecules rather than the soluble decoy receptor. Therefore, HpBARI2 combines steric blockade, conformational restriction and multivalent binding to potently and selectively inhibit ST2 signalling in the context of soluble ST2. This insight will guide design of improved therapeutics which target ST2.