Single Ig IL-1-related receptor (SIGIRR)

Single Ig IL-1-related receptor (SIGIRR), also known as TIR8, is a membrane-bound protein that serves as a critical negative regulator of the Interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) signaling pathways (UniProt, 2024, P59682). Structurally, it is distinguished from other IL-1R family members by having only one extracellular immunoglobulin domain and a unique C-terminal tail on its intracellular Toll/Interleukin-1 receptor (TIR) domain (Garlanda et al., 2009, Nature Reviews Immunology). SIGIRR functions by sequestering key adapter molecules such as MyD88 and IRAK, thereby preventing the assembly of functional signaling complexes and dampening the production of pro-inflammatory cytokines (Polentarutti et al., 2003, Journal of Biological Chemistry). It is highly expressed in epithelial tissues, particularly in the gastrointestinal tract and kidney, where it maintains immune homeostasis and prevents excessive inflammation-induced tissue damage (Xiao et al., 2007, Journal of Biological Chemistry). In clinical contexts, reduced expression or genetic variants of SIGIRR are associated with increased susceptibility to inflammatory bowel disease, systemic lupus erythematosus, and certain malignancies like colorectal cancer (Lech et al., 2010, Journal of the American Society of Nephrology). While there are currently no FDA-approved drugs specifically targeting SIGIRR, it is an active area of research for the development of anti-inflammatory mimetics and as a potential checkpoint in cancer immunotherapy (Molgora et al., 2020, Nature).

Other names

TIR8Single immunoglobulin domain-containing IL-1 receptor-related proteinSingle Ig domain-containing IL-1R-related molecule

Negative regulation of MyD88-dependent signaling by interfering with the recruitment of adapter proteins to the TLR/IL-1R complex.