Abstract
The 78-kDa glucose-regulated protein (GRP78) is a stress-inducible chaperone that resides primarily in the endoplasmic reticulum. GRP78 has been described to be released at times of cellular stress and as having extracellular properties that are anti-inflammatory or favor the resolution of inflammation. In the current study, we confirmed that GRP78 impaired the production of lipopolysaccharide-induced pro-inflammatory cytokines in GRP78-treated bone-marrow-derived dendritic cells (DCs). To explore the underlying mechanism, first of all, GRP78 was checked to be bound to the plasma membrane. Interestingly, such binding promoted endocytosis of toll-like receptor (TLR) 4 and reduction in TLR4 on the plasma surface had a key role in desensitization of GRP78-treated DCs to lipopolysaccharide. Given that cluster of differentiation (CD)14 is a crucial regulator of TLR4 endocytosis, interaction of GRP78 with CD14 was investigated next. Data showed that GRP78 co-localized with CD14 on the plasma membrane and glutathione-S-transferase-GRP78 precipitated CD14. In CD14 knockout mice, down-regulation of tumor necrosis factor-α and reduction in TLR4 on the plasma surface were abrogated in GRP78-treated DCs. Overall, these data suggested that GRP78 mediates endocytosis of TLR4 by targeting CD14 to favor the resolution of inflammation.
Highlights
The 78-kDa glucose-regulated protein (GRP78), referred to as immunoglobulin-binding protein (BiP), is a constitutively expressed resident protein of the endoplasmic reticulum (ER) present in all eukaryotic cells and belongs to the highly conserved heat shock 70 kDa protein (HSP70) family [1]
We found that cells treated with GRP78 downregulated the expression of cell surface TLR4 by enhanced endocytosis
After confirming that GRP78 could bind with unknown cell surface structures on dendritic cells (DCs), we examined whether GRP78 could interact with TLR4 and, if so, its role in TLR4-triggered responses
Summary
The 78-kDa glucose-regulated protein (GRP78), referred to as immunoglobulin-binding protein (BiP), is a constitutively expressed resident protein of the endoplasmic reticulum (ER) present in all eukaryotic cells and belongs to the highly conserved heat shock 70 kDa protein (HSP70) family [1]. GRP78 was initially identified as an “ER molecular chaperone” which protects cells against stress-induced apoptosis as a stress-inducible protein [2, 3]. Our previous work has shown that GRP78 overexpression can protect insulinoma NIT-1 cells from cytotoxic T-cell-mediated lysis [4] and enhance survival of CHO cells in response to serum deprivation and oxidative stress [5]. Upregulation of GRP78 is induced by ER stress, leading to its cell surface expression and secretion into the extracellular compartment [6]. Cell surface GRP78 forms complexes with a variety of cell-surface-anchored proteins (e.g., Cripto and T-cadherin) and extracellular ligands (e.g., activated α2-macroglobulin, Kringle 5, and Par-4) in tumor and endothelial cells leading to pro-survival or pro-apoptotic pathways [1, 7]. Secreted GRP78 exhibits immunoregulatory functions [8, 9]
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