Fig. 4

Schematic diagram depicting IL17RD (Sef) modulation of the TIR signaling pathway. IL17RD regulates TIR signaling by interfering with recruitment of upstream and downstream adapter proteins to modulate host immune response. In TLR signaling, IL17RD binds to plasma membrane TLR4 and endosomal TLR3 in resting cells. Upon recognition of extracellular and intracellular microbial components such as LPS and poly I:C, IL17RD associates with adapter proteins MyD88, Mal, TRIF and TRAM to modulate their interaction with TRAF6. Therefore, IL17RD indirectly suppresses the ubiquitination of TRAF6 to inhibit the activation of the canonical NF-κB and non-canonical IRF3 pathways and expression of target genes. With respect to signaling downstream of IL1 ligands from the TIR family, IL17RD regulates activation of the NF-κB pathway downstream of IL1α binding to IL1R, by associating with the IKKβ, IKBα and p50 subunits at the Golgi and restricting pathway activation