The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Maintaining proteostasis is the province of the proteostasis network, which consists of the cellular components that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental functional unit in biology with relevance to many diseases. Despite its importance, the human proteostasis network has until now lacked a precise definition, limiting our ability to interrogate proteostasis, integrate multiomic datasets, compare results across studies, or model proteostasis dysfunction in disease. To address this limitation, we have operationally defined the human proteostasis network by providing a comprehensive, annotated, and manually curated list of its components classified into nine Branches based on their function and localization - cytonuclear proteostasis, ER proteostasis, mitochondrial proteostasis, nuclear proteostasis, proteostasis network regulation, translation, extracellular proteostasis, the autophagy-lysosome pathway, and the ubiquitin-proteasome system - which we present in a series of three manuscripts of which this is the first. Overall, the proteostasis network annotation encompasses 3,151 components described by 4,043 annotations. Here, we present the 1,190 components that make up the first seven of these Branches, which comprise the compartment-based proteostasis network (cytonuclear, ER, mitochondrial, nuclear, and extracellular proteostasis), proteostasis network regulation, and translation. These Branches include chaperones, folding enzymes, systems for trafficking proteins, organelle-specific degradation systems, and the cell's translation machinery. This work provides a framework that will facilitate insights into how proteostasis is preserved in health, lost in aging and disease, and how it could be restored through pharmacological intervention.
