Proteostasis Network Systems Biology in Health and Disease

Proteomes of eukaryotic cells and tissues comprise a complex repertoire of diverse protein species that are organized in complex molecular machines and networks. Protein homeostasis, or proteostasis, describes the dynamic control of each protein’s concentration, fold, interaction profile, and subcellular localization in order to achieve and maintain native protein function.

The Proteostasis Network (PN) is an intricately regulated, modular yet interactive network uniting several highly conserved biological processes involved in maintenance of the healthy proteome. The ‘human chaperome’ for instance, the ensemble of ~300 chaperones and co-chaperones, is a central proteostasis network component and crucial determinant of the cellular protein folding and quality control environment in support of native proteome function. The role of a chaperome sub-network as a proteostasis safeguard in human aging and age-onset neurodegenerative disease has recently been described (Brehme et al. 2014). 

Emerging understanding of proteostasis signaling has revealed links to a variety of other diseases, from neurodegenerative, metabolic and cardiovascular to diseases of the immune system and cancer. Given the fundamental role of the PN in proteome maintenance new questions arise: • How is the PN altered in disease? • How does the network respond to drug action, or is it crucially involved in conferring drug sensitivity or resistance? • Do cellular or organismal proteostasis profiles determine drug response, disease susceptibility or progression trajectories? Strategically, our integrative research aims at a systems-level understanding of the structure and regulation of the PN throughout the human diseasome toward improved models, markers and therapeutic strategies of clinical value.
Selected references: