Methylglyoxal alters the function and stability of critical components of the protein quality control

Abstract

Background: Increased production and accumulation of methylglyoxal (MGO), as well as increased modification of proteins by glycoxidation, are hallmarks of aging and diabetes. MGO was shown to modify proteins and to contribute to the accumulation of damaged proteins that can be toxic to cells. However, the effect of MGO on the cell systems responsible for repairing or degrading damaged proteins is still unclear. In this study, the effect of MGO on the function of the ubiquitinproteasome system (UPS) and on molecular chaperones, two cooperative mechanisms associated with protein quality control, was investigated. Principal Findings: In this work it is shown that treatment of cells with MGO leads to accumulation of ubiquitin conjugates and depletion of free ubiquitin. Moreover, MGO significantly decreases the proteolytic activity of the 20S proteasome. Data further shows that MGO decreases the levels of the molecular chaperones Hsc70 and Hsp90 and leads to accumulation of CHIP-, Hsp40- and ubiquitin-containing aggregates. The formation of large aggregates containing CHIP is a consequence of its binding to misfolded proteins and to molecular chaperones. Moreover, dysfunction of the chaperones/CHIP/UPS axis is associated with accumulation of oxidized and argpyrimidine-modified proteins, which is likely to be associated with decreased cell viability. Interestingly, data further shows that MGO-induced stress induces the activation of heat shock factor-1 (Hsf-1), the main transcription factor involved in the regulation of the expression of heat shock proteins (HSPs) and cell response to stress. Conclusions: The data obtained in this work suggests that MGO impairs both the UPS and the protein quality control dependent on CHIP and molecular chaperones, leading to accumulation of toxic aggregates and increased cell death. However, these MGO-induced changes appear to elicit a response from the Hsf-1 system, which is crucial to help cells to cope with cellular stress and to re-establish homeostasis.