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Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability
Abstract
Chaperone proteins are thought to promote the correct folding and assembly of newly synthesized proteins and to facilitate restoration of the folded state under environmental conditions that favour protein denaturation. They are among the most ubiquitous and highly conserved of all proteins. The eukaryotic endoplasmic reticulum (ER) chaperone gp96 in particular has long been thought to be indispensable for cell survival. Here we report that a screen for genes required for the immune response to bacterial endotoxins has identified a B-cell line deficient in gp96. Absence of gp96 is compatible with cellular survival even under stress conditions and causes a defect in the formation of only a small subset of cell surface receptors. Toll-like receptors are retained intracellularly in the absence of gp96, explaining the unresponsiveness of the mutant to microbial stimuli.
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The absence of GRP94 did not affect cell viability or the general expression of surface protein in isolated mammalian cells.
“the absence of GRP94 did not affect cell viability or the general expression of surface protein in isolated mammalian cells”
From GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation (2015) · cites this paper as Randow and Seed, 2001
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”
The E4.126 clone was independently derived from 70Z/3 cells by ICR191 mutagenesis and also carries two frameshifting mutations in gp96.
“The E4.126 clone was independently derived from 70Z/3 cells by ICR191 mutagenesis, and also carries two frameshifting mutations in gp96.3,13”
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”
Comparison of gp96-knockout and gp96-reconstituted murine pre-B cells found that the cell surface expression of 29 proteins was decreased >3.0 fold in the absence of gp96.
“A comparison of gp96-knockout and gp96-reconstituted murine pre-B cells3,13 found that the cell surface expression of 29 proteins was decreased >3.0 fold in the absence of gp96.”
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.”
Surface localization of TLR6 was dependent on gp96.
“Surface localization of TLR6 was dependent on gp96 (Table 2), as reported.3,4,30”
Gp96 may be required for CD180/MD1 complex assembly, by analogy to TLR4/MD2, as in the absence of gp96, TLR4 and MD2 cannot associate.
“Gp96 may be required for CD180/MD1 complex assembly, by analogy to TLR4/MD2, as in the absence of gp96, TLR4 and MD2 cannot associate.3”
Several proteins were not dependent on gp96 for their surface expression, including CD44, ICAM1, CXCR4, IL7R and MHC class I allotypes, and this was confirmed by flow cytometry for CD44 and H2-Kb.
“Several proteins were not dependent on gp96 for their surface expression, including CD44, ICAM1, CXCR4, IL7R as well as MHC class I allotypes3,11 and this could be confirmed by flow cytometry for CD44 and H2-Kb (Figure 3).”
Gp96 is critical for proper folding and functional expression of a number of integrins and TLRs; in gp96-deficient cells, these proteins are minimally expressed at the cell surface as assessed by flow cytometry.
“Gp96 is critical for proper folding and functional expression of a number of integrins and TLRs; in gp96-deficient cells, these proteins are minimally expressed at the cell surface as assessed by flow cytometry.3,5”
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 data validated the dependence on gp96 for cell surface expression of integrins α4, αV, αL, and β2, and gp96 independence of integrins β1, α6 and α5.
“Our data was validated by confirming the dependence on gp96 for cell surface expression of integrins α4, αV, αL, and β2,2,3,9,11 and gp96 independence of integrins β1, α6 and α52 (Table 2 and Table S1, Supporting Information).”
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.”
Citations
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“However, the folding of integrins in vivo does not require ATP hydrolysis but ATP binding and direct interactions with BiP, as shown here and in previous studies (19, 43).”
Metadata
- Authors
- Randow, F., & Seed, B.
- Venue
- Nature Cell Biology
- Published
- 2001-09-11
- Volume
- 3
- Issue
- 10
- Pages
- 891-896
- ISSN
- 1465-7392
- 1476-4679
- Cited by
- 316
- References
- 2
- Language
- en
- Licence
- www.springer.com/tdm (tdm)
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