Figure 7.

Working model of the yeast response to gene mistranslations. Mistranslated proteins are folding substrates of molecular chaperones that compete with wild type client substrates for folding/refolding. Gradual accumulation of mistranslated proteins shifts the HSP-client binding equilibrium to the subpopulation of misfolded proteins, releasing client substrates from HSPs. This activates or inactivates natural HSP-client substrates depending on whether the HSP-client interaction is positive or negative. HSP substrate release deregulates cellular processes mediated by the HSP client proteins and remodels chaperone-chaperone networks, which are critical for cellular homeostasis. Increased protein folding/refolding and degradation increase ATP consumption leading to up-regulation of mitochondrial metabolism and ROS accumulation. Accumulation of mistranslated proteins in mitochondria also increases mitochondrial stress and ROS production. Mistranslated proteins that enter the secretory pathway accumulate in the ER and up-regulate ER resident chaperones, activating the UPR, further increasing ROS production. This leads to a deficit in protein secretion with consequences for cell membranes and cell wall structure and function. Aggregation of mistranslated proteins exacerbates proteotoxic stress, increases ATP consumption and activates the general stress response (ESR) through the transcription factors Msn2/4p and Yaps. Mistranslations also down-regulate ribosome biosynthesis, translational factors and CLIPS, exacerbating the negative consequences of mistranslations due to the critical role of CLIPS in folding newly synthesized proteins.

Paredes et al. BMC Biology 2012 10:55   doi:10.1186/1741-7007-10-55
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