Hsp40 Couples with the CSPa Chaperone Complex upon Induction of the Heat Shock Response

In response to a conditioning stress, the expression of a set of molecular chaperones called heat shock proteins is increased. In neurons, stress-induced and constitutively expressed molecular chaperones protect against damage induced by ischemia and neurodegenerative diseases, however the molecular basis of this protection is not known. Here we have investigated the crosstalk between stress-induced chaperones and cysteine string protein (CSPa). CSPa is a constitutively expressed synaptic vesicle protein bearing a J domain and a cysteine rich ‘‘string’ ’ region that has been implicated in the long term functional integrity of synaptic transmission and the defense against neurodegeneration. We have shown previously that the CSPa chaperone complex increases isoproterenol-mediated signaling by stimulating GDP/GTP exchange of Gas. In this report we demonstrate that in response to heat shock or treatment with the Hsp90 inhibitor geldanamycin, the J protein Hsp40 becomes a major component of the CSPa complex. Association of Hsp40 with CSPa decreases CSPa-CSPa dimerization and enhances the CSPa-induced increase in steady state GTP hydrolysis of Gas. This newly identified CSPa-Hsp40 association reveals a previously undescribed coupling of J proteins. In view of the crucial importance of stress-induced chaperones in the protectio