RHEB and gout: Importantly, we observed that IL-37 mutations within β-trefoil fold encoded by exons 4, 5, and 6, such as A123P, G153D, C160 but not N161S, which are initially discovered in gout patients, lost the ability to bind Rheb, implying that abnormal IL-37d-Rheb interaction is closely related with gout development and may facilitate gout pathogenesis29 (Fig. 4h, i).