Cellular protein homeostasis (or proteostasis) is maintained by a network of organelle-selective stress-responsive signaling pathways activated by the intracellular accumulation of misfolded proteins. These pathways primarily function through the activation of downstream transcription factors that induce genes involved in protein folding, trafficking and degradation pathways � the primary pathways involved in regulating cellular proteostasis. The capacity for stress-activated transcription factors to remodel cellular proteostasis suggests that exogenous manipulation of stress-responsive signaling could be used to prevent the pathological misfolding, mistrafficking, degradation or aggregation of destabilized, mutant proteins associated with human protein misfolding diseases. To explore this therapeutic strategy, we used destabilized domain technology to develop genetically-encoded, ligand-regulated stress-responsive transcription factors whose activity can be sensitively controlled in cellular disease models. Using this approach, we are exploring the transcriptional, proteomic, and functional impact of stress-responsive signaling on cellular proteostasis, revealing novel therapeutic approaches to treat human protein misfolding diseases.

Small molecule regulated transcription factors to understand stress responsive signaling

244th National Meeting (2012)

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