Modulation of Leucine-rich Repeats and Calponin Homology Domain-containing Protein 4 (Lrch4) Activity for Therapeutic Applications

NIH Inventors have recently discovered a novel Leucine-rich repeat and calponin homology domain-containing protein 4 (Lrch4) in a proteomic screen of the plasma membrane of lipopolysaccharide (LPS)-exposed macrophages. Expression data by RT-PCR revealed that all Lrch family members (1-4) are expressed in macrophages, but only Lrch4 was recruited into lipid rafts (signaling microdomains of the plasma membrane) by LPS. Lrch4 is the most highly expressed Lrch family member in mouse tissues. It is a predicted single-spanning transmembrane protein that is encoded by the Lrch4 gene in humans. The Lrch4 ectodomain is predicted to have a series of leucine-rich repeats, the motifs by which Toll like Receptors (TLR) are thought to bind microbial ligands. The human form of Lrch4 is 83% identical to murine Lrch4 and is predicted to have 680 amino acids and a molecular weight of 73 kDa.

NIH inventors have shown that Lrch4 is expressed on the plasma membrane of macrophages. They have determined that Lrch4 regulates pro-inflammatory signals (NF-kappaB activation, cytokine induction) emanating from all TLRs tested, and also regulates ligand-independent signals from MyD88. Further, LPS-induced p38, JNK, and NFkappaB activation are attenuated following Lrch4 knockdown, indicating that Lrch4 regulates upstream LPS signaling events. LPS-induced expression of the NF-kappaB-dependent cytokine TNFalpha was attenuated following Lrch4 knockdown at the level of both transcript and protein. Based on these and other findings, the inventors of this technology propose that Lrch4 may be a novel component of TLR receptor complexes and that modulation of Lrch4 activity might open up new opportunities for developing novel therapeutics for inflammatory diseases.