Cell stress response: activation of the aggresome pathway, HSPs, and transcriptional response. (a) Under nonstress conditions, protein degradation occurs through the proteasome. HDAC6 is sequestered by VCP/p97 and forms a basal complex with HSF1 and HSP90. This keeps HSF1 in its inactive form. (b) Inhibition of the proteasome leads to an increase of misfolded proteins. HDAC6 binds these ubiquitinated protein aggregates and the basal complex disassembles. This complex dissociation activates HSF1, which eventually activates HSPs. The protein aggregates are transported along the MTs to MTOC to form an aggresome and autophagic clearance is activated. HDAC6 can also modulate Hsp90 acetylation levels and affect the maturation of client proteins, such as the glucocorticoid and androgen receptors, impairing gene transcription activation.
