SUMMARY PARAGRAPH for HSP104
HSP104 encodes a general anti-stress chaperone of the HSP100 gene family (reviewed in 10). Unlike most chaperones that prevent proteins from aggregating, Hsp104p, in conjunction with the chaperone and co-chaperone Ssa1p and Ydj1p, helps to disassemble protein aggregates that have accumulated due to stress (5, 4). Hsp104p has also been shown to interact with the co-chaperones Sti1p, Cpr7p, and Cns1p (11).
HSP104 is expressed at very low levels under normal conditions but is induced upon stress (12). Transcriptional upregulation is independently mediated by the transcriptional activators Msn2p/Msn4p and Hsf1p, which bind to three stress response elements and two heat shock elements present in the HSP104 promoter (13).
Hsp104p is thought to exist in either inactive monomeric, dimeric, or trimeric forms or as an active, ring-shaped hexamer (reviewed in 10). During aggregate disassembly, substrate proteins are unfolded and subsequently threaded through this hexameric ring (14). Formation of the Hsp104p hexamer is nucleotide-dependent and regulated by NBD2, one of two Hsp104p nucleotide-binding domains (NBDs) (reviewed in 10 and 15). Although ATP hydrolysis by NBD2 is slow, ATPase activity of the other NBD, NBD1, is very high and provides the energy necessary to drive protein disaggregation (16). The state of Hsp104p ATP/ADP binding also regulates substrate affinity, with the ADP-bound state having low and the ATP-bound state having high polypeptide affinity (17).
HSP104 null mutations result in no obvious phenotype under normal conditions, but when exposed to stresses such as heat, ethanol, and radiation, these mutants have a markedly decreased rate of survival (2, 18). Expression of Hsp78p, the mitochondrial homolog of Hsp104p, in the cytosol of these mutants rescues them from heat damage and restores thermotolerance to the cells (19).
The effect of HSP104 expression has also been studied in yeast models of human disease, such as the prion disease Creutzfeldt-Jakob disease (OMIM) and Huntington disease (OMIM). HSP104 deletion strains are unable to propagate the yeast prions [PSI+], [PIN+], and [URE3] (the mutant protein forms of Sup35p, Rnq1p, and Ure2p, respectively) and it has been shown that both overexpression and underexpression of Hsp104p cures cells carrying the [PSI+] prion (reviewed in 20). Overexpression of HSP104 has been shown to reduce polyglutamine aggregation and toxicity in mammalian cells and to extend the lifespan of transgenic Huntington mice (21 and references contained therein).
Hsp104p homologs have been identified in bacteria, other fungi, and plants (6, 22, 23).
Last updated: 2006-06-28