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Heat Shock Protein gp96 Is a Master Chaperone for Toll-like Receptors and Is Important in the Innate Function of Macrophages
Abstract
gp96 is an endoplasmic reticulum chaperone for cell-surface Toll-like receptors (TLRs). Little is known about its roles in chaperoning other TLRs or in the biology of macrophage in vivo. We generated a macrophage-specific gp96-deficient mouse. Despite normal development and activation by interferon-gamma, tumor necrosis factor-alpha, and interleukin-1beta, the mutant macrophages failed to respond to ligands of both cell-surface and intracellular TLRs including TLR2, TLR4, TLR5, TLR7, and TLR9. Furthermore, we found that TLR4 and TLR9 preferentially interacted with a super-glycosylated gp96 species. The categorical loss of TLRs in gp96-deficient macrophages operationally created a conditional and cell-specific TLR null mouse. These mice were resistant to endotoxin shock but were highly susceptible to Listeria monocytogenes. Our results demonstrate that gp96 is the master chaperone for TLRs and that macrophages, but not other myeloid cells, are the dominant source of proinflammatory cytokines during endotoxemia and Listeria infections.
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Surface localization of TLR6 was dependent on gp96.
“Surface localization of TLR6 was dependent on gp96 (Table 2), as reported.3,4,30”
The chaperone activity of gp96 is selective, with targets including integrins, TLRs, IGFs, thyroglobulin and the platelet glycoprotein Ib-IX-V complex.
“However, the chaperone activity of gp96 is selective, with targets including integrins, toll-like receptors (TLRs), insulin-like growth factors (IGFs), thyroglobulin and the platelet glycoprotein Ib-IX-V complex.2−8”
The endoplasmic reticulum chaperone gp96 is required for the cell surface expression of a narrow range of proteins, including toll-like receptors (TLRs) and integrins.
“The endoplasmic reticulum chaperone gp96 is required for the cell surface expression of a narrow range of proteins, including toll-like receptors (TLRs) and integrins.”
The reported gp96 dependence of integrins α4, αV, αL, β2 and TLR6 and TLR4, and the lack of dependence of α6 and β1 integrins, were confirmed.
“We confirmed the reported gp96 dependence of integrins α4, αV, αL, β2 and toll-like receptors TLR6 and TLR4, and the lack of dependence of the α6 and β1 integrins.2−4,9,11”
Surface expression of TLR4 is dependent on gp96.
“One of the two peptides was quantified by both algorithms, with fold down-regulation ratios of 34.2 (Mascot) and 14.1 (Andromeda), suggesting that surface expression of TLR4 is dependent on gp96, as reported.3,4”
The known gp96 clients, integrins and TLRs, fail to reach the cell surface in the absence of gp96 due to misfolding; it is therefore likely that LDLR family members are similarly affected in the absence of gp96.
“The known gp96 clients, integrins and TLRs, fail to reach the cell surface in the absence of gp96 due to misfolding1−8—it is therefore likely that LDLR family members are similarly affected in the absence of gp96.”
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Metadata
- Authors
- Yang, Y., Liu, B., Dai, J., Srivastava, P. K., Zammit, D. J., Lefrançois, L., & Li, Z.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 26
- Issue
- 2
- Pages
- 215-226
- ISSN
- 1074-7613
- Cited by
- 410
- References
- 5
- Language
- en
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