Identification and characterization of a unique leucine-rich repeat protein (LRRC33) that inhibits Toll-like receptor-mediated NF-κB activation

• LRRC33 is a novel TLR homolog that contains 17 LRRs but lacks TIR domain.
• LRRs at the extracellular domain of LRRC33 is required for TLR interaction.
• Interaction of LRRC33 with TLR is critical for suppressing NF-κB and JNK activation.
• LRRC33 represents the first LRR-containing proteins in restraining inflammation.

Toll-like receptors (TLRs) are important initiators in innate immune responses against pathogenic microbes such as viruses, intracellular bacteria or parasites. Although the innate immune system is designed to fight infectious pathogens, excessive activation of TLR signaling may lead to unwarranted inflammation with hazardous outcomes. Mechanisms of restraining excessive inflammation and controlling homeostasis for innate immunity are the focus of intense study. Here we showed that LRRC33, a novel member of leucine-rich repeat (LRR) protein family, plays a critical role in desensitizing TLR signaling. LRRC33 is TLR homolog that contains 17 putative LRRs in the extracellular region but lacks a cytoplasmic Toll/IL-1 receptor (TIR) domain. Expression of LRRC33 appears to be ubiquitous with high level of expression found in bone marrow, thymus, liver, lung, intestine and spleen. The LRRs of LRRC33 is required for the interaction with TLR and its inhibitory effect on NF-κB and AP-1 activation as well as cytokine production. Our study sheds new insight into the TLR signaling and inflammatory response in development and human diseases.