Fig. 7: Proposed model of BLUE compound mode of action.
From: Molecular glues that inhibit deubiquitylase activity and inflammatory signaling
Interferon binding to IFNAR1 receptors triggers JAK–STAT signaling and an elevated immune response. IFN also initiates IFNAR1 receptor ubiquitylation (K63-linked), receptor internalization and lysosomal degradation. The BRISC–SHMT2 complex is required for deubiquitylation of IFNAR1. BRISC is recruited to IFNAR1 and IFNAR2 through interactions with SHMT2 to promote sustained IFN signaling and inflammation. BLUE compounds (blue stars) promote the formation of a BRISC dimer complex, which sterically hinders SHMT2 and polyubiquitin binding. Some graphics in this image were generated with BioRender.com.
