HSP70 and HSP90 recognize distinct protein-folding intermediates within a cell. Mining available data sets, the researchers found that mutants predominantly recognized by HSP70 (compared to HSP90) were associated with more severe clinical phenotypes across diverse diseases. This could be because protein variants with more severely compromised structures are better substrates for HSP70, which recognizes more immature and therefore more extensively unfolded proteins than HSP90. Indeed, the majority of HSP90-engaged mutants retained some level of protein activity in functional assays, whereas almost all HSP70-engaged mutants were non-functional in these assays.
Next, the team investigated the relationship between chaperone engagement and disease severity in Fanconi anaemia, a genome instability disorder known to be both clinically and genetically heterogeneous. FANCA is the most frequently compromised protein in Fanconi anaemia. The functional severity of FANCA mutations was assessed in patient-derived fibroblast cell lines (GM6914 cells), which as a result of FANCA deficiency are hypersensitive to genotoxic drugs. GM6914 cells engineered to express HSP70-engaged FANCA mutants remained FANCA-deficient. By contrast, cells that expressed HSP90-engaged mutant proteins behaved similarly to wild-type cells. Furthermore, treating HSP90-engaged FANCA mutant cells with HSP90 inhibitors increased their sensitivity to genotoxic drugs, as did subjecting these cells to environmental stresses that compromise HSP90 activity. These data suggest that HSP90 buffers the effects of HSP90-engaged mutations and thereby preserves mutant protein functionality.
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