HSP27, cell stress, and hormesis: From mammals to humanized yeast models

Hormesis is a biphasic dose-response phenomenon characterized by beneficial or stimulatory effects at low exposure levels to a stressor, followed by inhibitory or toxic effects at higher doses. This effect is related to the level of oxidative stress in the cell. Human HSPB1 (HSP27) is a small heat shock protein involved in the oxidative stress response, whose overexpression correlates with increased longevity in mammalian models. HSP27 protects neurons from damage caused by protein aggregation observed in neurodegenerative diseases; however, this same survival capability also favors tumor cells, hindering chemotherapeutic treatment. This review describes HSP27 and demonstrates that the humanized yeast model can aid in understanding the function of this protein, which protects neurons and enhances tumor survival. HSP27 exhibits a dose-dependent hormetic effect when expressed at varying levels in yeast. This expression-dependent response enhances longevity, proteasome activity, and resistance to thermal and oxidative stresses. The humanized yeast model may help elucidate the relationship between the quaternary structure of the protein and its hormetic effect. In addition, the humanization of partial or complete pathways involved in both neurodegenerative diseases and apoptosis may provide a way to identify small molecules that enhance neuronal protection and potentially inhibit HSP27's pro-survival function in cancer treatment.