Heat shock protein gp96 regulates Toll-like receptor 9 proteolytic processing and conformational stability Journal Article
| Authors: | Brooks, J. C.; Sun, W.; Chiosis, G.; Leifer, C. A. |
| Article Title: | Heat shock protein gp96 regulates Toll-like receptor 9 proteolytic processing and conformational stability |
| Abstract: | Nucleic acid-sensing Toll-like receptors (TLRs) initiate innate immune responses to foreign RNA and DNA, yet can detect and respond to host DNA. To avoid autoimmune pathologies, nucleic acid sensing TLRs are tightly regulated. TLR9 primarily resides in the endoplasmic reticulum, traffics to endosomes, is proteolytically processed and responds to DNA. The heat shock protein gp96 is one of several accessory proteins that regulate intracellular trafficking of TLR9. In the absence of gp96, TLR9 fails to exit the endoplasmic reticulum, and therefore gp96-deficient macrophages fail to respond to CpG DNA. However, absence of gp96 precludes studies on potential chaperoning functions of gp96 for TLR9. Here we demonstrate that pharmacologic interference with gp96 function inhibits TLR9 signaling. TLR9 remains associated with gp96 during intracellular trafficking, and gp96-specific inhibitors increase TLR9 sensitivity to proteolytic degradation. We propose that gp96 is critical for both TLR9 egress from the ER, and for protein conformational stability in the endosomal compartment. These studies highlight the importance of examining gp96-specific inhibitors for modulating TLR9 activation, and the treatment autoimmune diseases. © 2012 Elsevier Inc. |
| Keywords: | human cell; protein conformation; protein function; animals; mice; cell compartmentalization; protein degradation; protein stability; endoplasmic reticulum; dna; membrane glycoproteins; cpg islands; innate immunity; conformation; macrophage; autoimmune diseases; autoimmune disease; cell transport; toll-like receptor 9; endosome; chaperone; toll like receptor 9; hek293 cells; heat-shock proteins; glycoprotein gp 96; heat shock protein; proteolysis |
| Journal Title: | Biochemical and Biophysical Research Communications |
| Volume: | 421 |
| Issue: | 4 |
| ISSN: | 0006-291X |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 2012-05-18 |
| Start Page: | 780 |
| End Page: | 784 |
| Language: | English |
| DOI: | 10.1016/j.bbrc.2012.04.083 |
| PROVIDER: | scopus |
| PMCID: | PMC3358552 |
| PUBMED: | 22554506 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 June 2012" - "CODEN: BBRCA" - "Source: Scopus" |
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