TLR folding by chaperones GP96 and CNPY3

Stable Identifier
R-HSA-1678923
Type
Reaction
Species
Homo sapiens
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GP96 (also known as GRP94, HSP90b1), a paralogue of HSP90 in the endoplasmic reticulum, acts as a chaperone for some integrines and Toll-like receptors. Macrophages or B-cells from gp96 knockout mice have abrogated function of TLR2, 4, 5, 7 and 9, but not TLR3 (Yang Y et al 2007, Liu B and Li Z 2008, Staron M et al 2010). GP96 interacts with TLRs and integrines via its C-terminal hydrophobic domain, formed by residues 652-678 (Wu S et al 2012). GP96 functions as a V-shaped dimer in ATP-dependent manner, however it remains unclear how ATP hydrolysis-dependent conformational changes of GP96 are regulated (Li Z and Srivastava PK 1993).

GP96 forms a complex with co-chaperone CNPY3, also known as PRAT4A. GP96-CNPY3 promotes the proper post-translational ectodomain folding of TLRs, but not TLR3 (Liu B et al 2010).

Literature References
PubMed ID Title Journal Year
17275357 Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages

Yang, Y, Liu, B, Dai, J, Srivastava, PK, Zammit, DJ, Lefrançois, L, Li, Z

Immunity 2007
18509083 Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin

Liu, B, Li, Z

Blood 2008
22223641 The Molecular Chaperone gp96/GRP94 Interacts With Toll-Like Receptors And Integrins Via Its C-Terminal Hydrophobic Domain

Wu, S, Hong, F, Gewirth, D, Guo, B, Liu, B, Li, Z

J Biol Chem 2012
20865800 Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone

Liu, B, Yang, Y, Qiu, Z, Staron, M, Hong, F, Li, Y, Wu, S, Li, Y, Hao, B, Bona, R, Han, D, Li, Z

Nat Commun 2010
8344253 Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation

Li, Z, Srivastava, PK

EMBO J 1993
19965672 gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis

Staron, M, Yang, Y, Liu, B, Li, J, Shen, Y, Zúñiga-Pflücker, JC, Aguila, HL, Goldschneider, I, Li, Z

Blood 2010
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