The Heat Shock Protein gp96 play a multifaceted role in regulating Toll-like receptor 9 (136.40)

Abstract

Abstract Inappropriate activation and failure to inactivate Toll-like receptors (TLRs) contribute to immune mediated pathology. Nucleic acid sensing TLRs, including TLR9, are tightly regulated to prevent self DNA and RNA recognition, which can contribute to autoimmune disease. The overall goal of our research is to determine the molecular mechanisms governing nucleic acid sensing TLRs using TLR9 as a model. Regulation of TLR9 includes control of intracellular trafficking by association with proteins such as the endoplasmic reticulum chaperone gp96. Obligate proteolytic cleavage of TLR9 to an 80 kDa form, p80, precedes TLR9 recognition of CpG DNA. Here we show that in the absence of gp96, there is a failure to generate p80. Furthermore, gp96 traffics with TLR9 to the endosomal compartment. Dissociation of gp96 from TLR9 using specific inhibitors leads to rapid degradation of the receptor and inhibition of signaling. CpG DNA pull down experiments demonstrate that gp96 is associated with the ligand-bound form of the receptor suggesting it contributes to CpG DNA recognition. We provide a model where gp96 plays a multifaceted role in TLR9 biology. These studies have major implications for pharmacologically manipulating the levels of active and inhibitory forms of TLR9 and other nucleic acid sensing TLRs, which will likely uncover novel therapeutic interventions for autoimmune diseases. AI076588 and AI076588-S1 (CAL).