Toll-like receptor-2 ligand peptidoglycan upregulates expression and ubiquitin ligase activity of CHIP through JNK pathway.

BACKGROUND Peptidoglycan (PGN) is a component of cell wall in Gram-positive bacteria that stimulates inflammatory responses through Toll-like receptor 2 (TLR2). The carboxyl terminus of constitutive heat shock cognate 70 (HSC70)-interacting protein (CHIP, also known as Stub1) is a U-box-type E3 ubiquitin ligase, which plays an important role in protein quality control and inflammation through ubquitin-mediated proteasomal degradation. However, it is unclear whether TLR2 agonist PGN regulates the expression and activation of CHIP. METHODS/RESULTS In this study, we showed that PGN significantly up-regulated the expression of CHIP in both mRNA and protein levels in RAW264.7 cells in a time-dependant manner, and the expression of CHIP induced by PGN was abolished in TLR2 knockout macrophages. No significant change in CHIP was observed after lipopolysaccharide (LPS, TLR4 agonist) and cytosine-phosphorous-guanine oligonucleotide (CpG ODN, TLR9 agonist) treatment. Moreover, PGN markedly induced the expression and activity of CHIP in macrophages, whereas this effect was attenuated by SP600125, a selective inhibitor of JNK. CONCLUSION Our study for the first time demonstrates that TLR2 activation enhances the expression and activity of CHIP through JNK signaling pathway.