proteostasis

Proteostasis, or protein homeostasis, describes the cellular network that controls the biogenesis, folding, trafficking, assembly, and degradation of proteins to maintain a functional proteome. It integrates protein synthesis, maturation in the endoplasmic reticulum, quality control, and removal of damaged or misfolded proteins, preventing aggregation that can disrupt cellular function.

Key components include molecular chaperones (for example Hsp70, Hsp90, small heat shock proteins) that assist folding and prevent aggregation; the ubiquitin-proteasome system that tags misfolded proteins with ubiquitin for degradation by the 26S proteasome; and the autophagy-lysosome system for bulk and selective degradation including macroautophagy and chaperone-mediated autophagy. ER quality control and ER-associated degradation monitor proteins entering the secretory pathway. The proteostasis network is dynamically regulated by stress-responsive signaling pathways such as the heat shock response, the unfolded protein response in the endoplasmic reticulum, and the integrated stress response, which coordinate transcriptional and translational changes to restore homeostasis.

Dysfunction of proteostasis is associated with aging and disease. Chronic proteostasis failure can lead to protein aggregation seen in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, as well as cataracts and certain myopathies. Conversely, cancer cells often rely on an altered proteostasis network to cope with high protein synthesis and mutations.

Research and therapeutic approaches aim to bolster proteostasis by inducing chaperones, modulating degradation pathways, or enhancing autophagy; such strategies include proteostasis regulators, proteasome modulators, and autophagy activators.