Abstract
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.
Highlights
The heat-shock response is a process that is evolutionarily conserved, has a rapid onset, is short-term and is essential for cells to survive under conditions of stress
C-terminus of Hsc70-interacting protein (CHIP) is known to activate heat-shock factor 1 (HSF1) and confer protection against heat shock (Dai et al, 2003). Because both CHIP and malin are E3 ubiquitin ligases, and both interact with Hsp70 and promote the clearance of misfolded proteins (Garyali et al, 2009; Jana et al, 2005), we addressed the possible role of Lafora disease (LD)-causing proteins in the heat-shock response
Laforin and malin translocate to nucleus upon heat shock CHIP, a predominantly cytoplasmic protein, is known to associate with Hsp70 and translocate to the nucleus when the cells are exposed to heat shock (Dai et al, 2003)
Summary
The heat-shock response is a process that is evolutionarily conserved, has a rapid onset, is short-term and is essential for cells to survive under conditions of stress It is characterized by an increase in the cellular level of molecular chaperones known as heat-shock proteins (HSPs) (Akerfelt et al, 2010). There appears to be a delicate balance between the demand and the supply of HSPs, and HSPs are rapidly induced when the cells are exposed to unfolded protein stress This is primarily achieved, at the transcriptional level, by heat-shock factor 1 (HSF1), a transcription factor that binds to heat-shock elements present in the promoter region of genes encoding HSPs (Akerfelt et al, 2010). Besides HSPs, co-chaperones, such as immunophilins, Hip, Hop and the C-terminus of Hsc70-interacting protein (CHIP), among others, are known to regulate the activation and/or the attenuation of HSF1, suggesting that HSF1 exists as a heterocomplex with a diverse set of regulatory proteins (Carrello et al, 1999; Zou et al, 1998; Bharadwaj et al, 1999; Ballinger et al, 1999)
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