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gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis
Abstract
Integrins contribute to lymphopoiesis, whereas Toll-like receptors (TLRs) facilitate the myeloid replenishment during inflammation. The combined role of TLRs and integrin on hematopoiesis remains unclear. gp96 (grp94, HSP90b1) is an endoplasmic reticulum master chaperone for multiple TLRs. We report herein that gp96 is also essential for expression of 14 hematopoietic system-specific integrins. Genetic deletion of gp96 thus enables us to determine the collective roles of gp96, integrins, and TLRs in hematopoiesis. We found that gp96-null hematopoietic stem cells could support long-term myelopoiesis. B- and T-cell development, however, was severely compromised with transitional block from pro-B to pre-B cells and the inability of thymocytes to develop beyond the CD4−CD8− stage. These defects were cell-intrinsic and could be recapitulated on bone marrow stromal cell culture. Furthermore, defective lymphopoiesis correlated strongly with failure of hematopoietic progenitors to form close contact with stromal cell niche and was not the result of the defect in the assembly of antigen receptor or interleukin-7 signaling. These findings define gp96 as the only known molecular chaperone to specifically regulate T- and B-cell development.
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The normal cell surface expression of integrin α1 and decreased expression of integrin β3 in gp96-deficient cells contrasts with a previous report.
“The normal cell surface expression of integrin α1 and decreased expression of integrin β3 in gp96-deficient cells contrasts with a previous report.2”
Many integrins require chaperoning by gp96, while some α- and β-integrins are gp96 independent.
“While many integrins require chaperoning by gp96, some α- and β-integrins are gp96 independent.2,9”
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 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 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 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
- Staron, M., Yang, Y., Liu, B., Li, J., Shen, Y., Zúñiga-Pflücker, J. C., Aguila, H. L., Goldschneider, I., & Li, Z.
- Affiliations
- Department of Immunology, University of Connecticut School of Medicine, Farmington; and
- Department of Immunology, University of Toronto, Sunnybrook Research Institute, Toronto, ON
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-03-25
- Volume
- 115
- Issue
- 12
- Pages
- 2380-2390
- ISSN
- 0006-4971
- 1528-0020
- Cited by
- 120
- References
- 1
- Language
- en
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