BAS/BSCR5 TILRR potentiates interleukin-1-induced anti-apoptosis
The pathogenesis of atherosclerosis is determined, in part, by inflammatory responses, induced through members of the Toll-like and interleukin (IL)-1 receptor family and controlled by NF-κB. We have identified a novel IL-1RI co-receptor, TILRR, which enhances the IL-1-induced activation of NF-κB by increasing receptor-expression enhanced recruitment of the MyD88 adaptor during activation.1 Here we investigate the role of TILRR on the anti-apoptotic effects controlled by NF-κB. The results showed that TILRR reduces caspase-3 activity and enhances IL-1-induced phosphorylation of AKT. Alanine scanning mutagenesis of the IL-1 receptor TIR domain demonstrated that TILRR amplifies inflammatory responses through the membrane proximal part of the cytoplasmic portion, the so-called box 1, while the anti-apoptotic response is regulated through the central portion of the TIR domain, the so-called box 2. Similarly, alanine scanning mutagenesis of the TILRR core protein, targeting conserved residues with predicted effects on secondary structure, demonstrated distinct control of inflammatory and anti-apoptotic intermediates. These results demonstrate that TILRR amplification involves selective control of NF-κB-regulated inflammatory and anti-apoptotic responses, and are consistent with induction of discrete conformational changes in the IL-1 receptor complex through TILRR association.
Funding BHF and the BBSRC.