Heat shock factor 1 (HSF1) specifically potentiates c-MYC-mediated transcription independently of the canonical heat shock response

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SUMO-1 modification increases human SOD1 stability and aggregation

The mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) cause approximately 20% cases of familial amyotrophic lateral sclerosis (FALS), characterized by selective loss of motor neurons. Mutant SOD1 forms inclusions in tissues from FALS patients. However, the precise mechanism of the accumulation of mutant SOD1 remains unclear. Here we show that human SOD1 is a substrate modified by SUMO-1. A conversion of lysine 75 to an arginine within a SUMO consensus sequence in SOD1 completely abolishes SOD1 sumoylation. We further show that SUMO-1 modification, on both wild-type and mutant SOD1, increases SOD1 steady state level and aggregation. Moreover, SUMO-1 co-localizes onto the aggregates formed by SOD1. These findings imply that SUMO-1 modification on lysine 75 may participate in regulating SOD1 stability and its aggregation process. Thus, our results suggest that sumoylation of SOD1 may be involved in the pathogenesis of FALS associated with mutant SOD1.     

Gene bookmarking by the heat shock transcription factor programs the insulin-like signaling pathway

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Alpha-helix 1 in the DNA-binding domain of heat shock factor 1 regulates its heat-induced trimerization and DNA-binding

Heat shock factor 1 (HSF1) primarily regulates various cellular stress responses. The role of α-helix1 (H1) in its DNA-binding domain (DBD) during HSF1 activation remains unknown. Here, HSF1 lacking H1 loses its heat-induced activity, suggesting the importance of the latter. Furthermore, the CD spectra and AMBER prediction show that this H1 deficiency does not change the structure of HSF1 monomer, but does impact its heat-induced trimerization. Point mutation showed that Phe18 in H1 interacts with Tyr60, and that Trp23 interacts with Phe104 by an aromatic-aromatic interaction. Thus, the presence of H1 stabilizes the DBD structure, which facilitates the heat-induced trimerization and DNA-binding of HSF1.