Protein quantity-quality balance licenses growth

One of the cellular defensivemechanisms against proteotoxic stress is the evolutionarily conserved proteotoxic stress response (PSR) or heat-shock response (HSR). Through up-regulation of molecular chaperones or heat-shock proteins (HSPs), the PSR empowers cells to repair and/or dispose of misfolded and aggregated proteins, thereby enduring stressful environments. Beyond being vital to stress resistance, the PSR has been implicated in a wide array of human pathological conditions, including cancer and neurodegenerative disorders. The master transcriptional regulator of the PSR is heat shock factor 1 (HSF1). Unsurprisingly, the HSF1-mediated PSR plays a pivotal role in preserving cellular proteome homeostasis or proteostasis. Two central factors governing cellular proteostasis are protein quantity and quality.While HSPs ensure the quality of cellular proteome, the mammalian target of rapamycin complex 1 (mTORC1) critically controls protein quantity. Stimulated by growth factors and nutrients, mTORC1 prompts protein translation by phosphorylating both the ribosomal S6 kinase (S6K) and the eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1). By contrast, a diversity of insults, including genotoxic, hypoxic, metabolic, and oxidative stress, all suppress mTORC1 through activation of either the AMP-activated protein kinase (AMPK) or the tuberous sclerosis complex 1/2 (TSC1/2). Despite its crucial role in controlling protein biosynthesis, surprisingly, little is known of howmTORC1 senses and responds to proteotoxic stress.