Proteostase

Proteostase, also known as proteostasis, refers to the cellular processes that control the synthesis, folding, trafficking, modification, and degradation of proteins to maintain a functional proteome. The proteostatic network coordinates production with quality control, ensuring proteins attain and retain their correct structure and location.

Core components include molecular chaperones that assist protein folding, such as heat shock proteins, the ubiquitin–proteasome system that marks and degrades misfolded or damaged proteins, and the autophagy–lysosome pathway that handles larger aggregates and organelles. In the endoplasmic reticulum, the unfolded protein response detects accumulation of misfolded proteins and adjusts folding capacity and degradation through signaling by IRE1, PERK, and ATF6.

Proteostatic regulation is dynamic and interconnected with cellular stress responses. Transcription factors such as HSF1 induce chaperone expression, while UPR signaling coordinates expansion of folding capacity, clearance, and, if stress persists, cell fate decisions. Mitochondrial proteostasis (mitoproteostasis) and cytosolic quality control systems also contribute to maintaining protein homeostasis across cellular compartments.

Impairment of proteostasis with aging or disease can lead to the accumulation of misfolded or aggregated proteins and cellular dysfunction. It is linked to neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases, as well as to aging, cancer, and metabolic disorders.

Research on proteostase seeks strategies to bolster protein quality control, including activators of chaperones, modulators of the ubiquitin–proteasome system or autophagy, and approaches that enhance ER and mitochondrial quality control, with the aim of delaying aging and treating proteopathy-related diseases.