Protein homeostasis (proteostasis) is maintained by the so-called proteostasis network that coordinates the rate of protein synthesis, folding, and degradation. Proteins are subject to cellular damage as a result of intracellular or extracellular insult. As the accumulation of damaged proteins impairs cellular function, cells have developed sophisticated quality control mechanisms to maintain proteome integrity: Accumulation of damaged/misfolded proteins induces stress responsive pathways, which in turn attenuate translation to decrease protein synthesis rate; increase the abundance of chaperones to facilitate protein (re-) folding; and finally, stimulate the protein degradation machinery (the ubiquitin-proteasome system and autophagy) to secure the elimination of damaged proteins. If these mechanisms fail to restore homeostasis, cells will undergo apoptosis.
In cancer, a multitude of intracellular (e.g. genomic instability, hyperactivated mTOR signaling, ROS) and extracellular stresses (e.g. low levels of oxygen and nutrients) continuously challenges proteome integrity, resulting in the constant activation of stress response pathways. Cancer cells can benefit from the activation of stress pathways as they increase stress tolerance and thus contribute to positive selection of aggressive phenotypes. On the other hand, the increased stress level is believed to render cancer cells more susceptible to drugs that target the proteostasis network offering a therapeutic window. Several drugs are designed aiming to disturb the proteostasis network (e.g. proteasome or HSP inhibitors), however, tumors often develop resistance. Current research aims to better understand the complexity of and crosstalk between the proteostasis network to reveal compensatory mechanisms that could be targeted to overcome resistance.
Did you know that when organelle specific protein quality control mechanisms fail, the entire organelle or damaged parts may be eliminated by specialized forms of autophagy (mitophagy or ER-phagy) to limit cellular damage?
Did you know that a large portion of the human proteome function in proteostasis networks?