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The heat-shock response is a conserved cellular process characterized by the induction of a unique group of proteins known as heat-shock proteins. One of the primary triggers for this response, at least in mammals, is heat-shock factor 1 (HSF1)--a transcription factor that activates the transcription of heat-shock genes and confers protection against stress-induced cell death. In the present study, we investigated the role of the phosphatase laforin and the ubiquitin ligase malin in the HSF1-mediated heat-shock response. Laforin and malin are defective in Lafora disease (LD), a neurodegenerative disorder associated with epileptic seizures. Using cellular models, we demonstrate that these two proteins, as a functional complex with the co-chaperone CHIP, translocate to the nucleus upon heat shock and that all the three members of this complex are required for full protection against heat-shock-induced cell death. We show further that laforin and malin interact with HSF1 and contribute to its activation during stress by an unknown mechanism. HSF1 is also required for the heat-induced nuclear translocation of laforin and malin. This study demonstrates that laforin and malin are key regulators of HSF1 and that defects in the HSF1-mediated stress response pathway might underlie some of the pathological symptoms in LD.

Malin and laforin are essential components of a protein complex that protects cells from thermal stress