SIGIRR Gene - Structure, Function, and Clinical Significance

SIGIRR (Single Ig and TIR domain containing receptor) is a protein-coding gene that encodes a member of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) superfamily. Unlike most family members, SIGIRR lacks a cytoplasmic Toll/IL-1 receptor (TIR) domain and functions as a negative regulator of TLR and IL-1R signaling pathways. It inhibits NF-κB activation and pro-inflammatory cytokine production, playing a critical role in maintaining immune homeostasis and preventing excessive inflammation. SIGIRR is widely expressed in epithelial tissues and immune cells, and its dysregulation is implicated in inflammatory diseases, autoimmune disorders, and cancer.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Toll-like receptor signaling pathway (KEGG: hsa04620)

• Interleukin-1 signaling pathway (Reactome: R-HSA-446652)

• NF-kappa B signaling pathway (KEGG: hsa04064)

• MyD88-independent TLR4 signaling (Reactome: R-HSA-166166)

SIGIRR is a 410-amino acid transmembrane protein with a single extracellular immunoglobulin (Ig) domain and a cytoplasmic TIR domain. It acts as a decoy receptor by sequestering signaling adaptors like MyD88 and TRAF6, thereby inhibiting downstream NF-κB and MAPK activation. The protein is expressed in epithelial cells, dendritic cells, and macrophages, where it dampens inflammatory responses. Structural studies show that the TIR domain of SIGIRR lacks key residues required for signaling, enabling its inhibitory function. Post-translational modifications include glycosylation and phosphorylation, which modulate its stability and activity.