Abstract
Hsp90 participates in many distinct aspects of cellular functions and accomplishes these roles by interacting with multiple client proteins. To gain insight into the interactions between Hsp90 and its clients, here we have reduced the protein level of Hsp90 in avian cells by gene targeting in an attempt to elicit the otherwise undetectable (because of the vast amount of cellular Hsp90) Hsp90-interacting proteins. Hsp90beta-deficient cells can grow, albeit more slowly than wild-type cells. B cell antigen receptor signaling is multiply impaired in these mutant cells; in particular, the amount of immunoglobulin M heavy chain protein is markedly reduced. Furthermore, serum activation does not promote ERK phosphorylation in Hsp90beta-deficient cells. These multifaceted depressive effects seem to be provoked independently of each other and possibly recapitulate the proteome-wide in vivo functions of Hsp90. Reintroduction of the Hsp90beta gene efficiently restores all of the defects. Unexpectedly, however, introducing the Hsp90alpha gene is also effective in restoration; thus, these defects might be caused by a reduction in the total expression of Hsp90 rather than by loss of Hsp90beta-specific function.
Highlights
Living cells continuously cope with protein folding and assembly
Southern blot analysis indicated that the constructs were properly targeted (Fig. 1B), and this result was corroborated by Northern blotting (Fig. 1C)
Hsp90 is relatively unique among molecular chaperones in that its client proteins seem to be restricted to a select group of proteins such as protein kinases and transcription factors [7,8,9,10,11,12]
Summary
Living cells continuously cope with protein folding and assembly. Because cell fate (e.g. proliferation, differentiation and even death) is determined and implemented by a plethora of varied proteins, the folding and assembly of these proteins are crucial to the life of a cell. The developmental deficiency observed in the Hsp90 mutant embryos may be attributable to a lack of specific functions that are fulfilled by only Hsp90 [25]; alternatively, the reduced expression level of Hsp may impinge on a specific aspect of the placental development. The expression level of the immunoglobulin (Ig) M heavy chain is profoundly reduced These defects can be efficiently corrected by reintroducing the Hsp90 gene and by introducing the Hsp90␣ gene; the defects observed in these cells are derived mainly from a reduction in the Hsp content and not from a loss of Hsp90-specific function
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