Abstract
It is conceivable that stimulating proteasome activity for rapid removal of misfolded and oxidized proteins is a promising strategy to prevent and alleviate aging-related diseases. Sulforaphane (SFN), an effective cancer preventive agent derived from cruciferous vegetables, has been shown to enhance proteasome activities in mammalian cells and to reduce the level of oxidized proteins and amyloid β-induced cytotoxicity. Here, we report that SFN activates heat shock transcription factor 1-mediated heat shock response. Specifically, SFN-induced expression of heat shock protein 27 (Hsp27) underlies SFN-stimulated proteasome activity. SFN-induced proteasome activity was significantly enhanced in Hsp27-overexpressing cells but absent in Hsp27-silenced cells. The role of Hsp27 in regulating proteasome activity was further confirmed in isogenic REG cells, in which SFN-induced proteasome activation was only observed in cells stably overexpressing Hsp27, but not in the Hsp27-free parental cells. Finally, we demonstrated that phosphorylation of Hsp27 is irrelevant to SFN-induced proteasome activation. This study provides a novel mechanism underlying SFN-induced proteasome activity. This is the first report to show that heat shock response by SFN, in addition to the antioxidant response mediated by the Keap1-Nrf2 pathway, may contribute to cytoprotection.
Highlights
The ubiquitin-proteasome system (UPS)2 is a nonlysosomal protein degradation mechanism that plays a primary role in the control of protein turnover in mammalian cells as well as in the removal of abnormal proteins [1, 2]
SFN-enhanced proteasome activity in murine neuroblastoma cells and induction of proteasome subunit PSMB5 have been attributed to NF-E2-related factor 2 (Nrf2)
A report revealed that a variety of heat shock proteins (HSPs) and proteasome subunits, including heat shock protein 27 (Hsp27) and PSMB5, are significantly induced by WY-14643, a peroxisome proliferator-activated receptor ␣ inducer, in nrf2-null mice [32]
Summary
The ubiquitin-proteasome system (UPS) is a nonlysosomal protein degradation mechanism that plays a primary role in the control of protein turnover in mammalian cells as well as in the removal of abnormal proteins [1, 2]. This tightly regulated proteasome complex is involved in the cell cycle, cellular signal transduction, transcriptional regulation, stress responses, cell differentiation, and metabolic adaptation [3, 4]. Expression of heat shock protein 27 (Hsp27) [19], a small HSP that can be induced by a wide variety of stresses including heat shock, oxidative stress, anticancer drugs, and radiation [20], has been associated with elevated
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