A Comprehensive Enumeration of the Human Proteostasis Network. 1. Components of Translation, Protein Folding, and Organelle-Specific Systems

Abstract

The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, approximately 2,500 genes that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental entity in biology with direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, which hinders its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. Here, we provide a curated list of 959 unique genes that comprise the protein synthesis machinery, chaperones, folding enzymes, systems for trafficking proteins into and out of organelles, and organelle-specific degradation systems. In subsequent manuscripts, we will delineate the human autophagy-lysosome pathway, the ubiquitin-proteasome system, and the proteostasis networks of model organisms.

A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway

“…We previously introduced a taxonomic annotation system for the proteostasis network. 12 This system was constructed to convey at a glance a component’s role in proteostasis. It consists of five levels: Branch, Class, Group, Type, and Subtype.…”

“…There are eight Branches of the proteostasis network (PN; Figure 1), six of which we described previously (cytonuclear proteostasis, ER proteostasis, mitochondrial proteostasis, nuclear proteostasis, cytosolic translation, and proteostasis network regulation). 12 The ALP is the seventh Branch of the proteostasis network, and the UPS is the eighth. The Class, Group, Type and Subtype annotations give increasingly specific descriptions of a component’s role in proteostasis.…”

“…The first installment of this list was reported recently and included the machinery of protein synthesis, chaperones, folding enzymes, the systems for trafficking proteins into and out of organelles, and organelle-specific degradation pathways. 12 Here we report the next installment, a comprehensive list of the components of the autophagy-lysosome pathway (ALP). The ALP is one of two major systems for the degradation of proteins (the other being the ubiquitin-proteasome system, or UPS, which is the subject of an upcoming manuscript).…”

Single-cell expression predicts neuron specific protein homeostasis networks

“…A list of human genes encoding subunits of ion channels was taken from the ModelDB database (Mc-Dougal et al, 2017). A curated list of human chaperones (Brehme et al, 2014;Shemesh et al, 2021) was obtained from the Proteostasis Consortium (Elsasser et al, 2022), and a list of genes in the human ubiqutin-dependent degradation system was compiled from the hUbiquitome (Du et al, 2011) and UbiNet2.0 (Li et al, 2021) databases.…”

Mitochondrial dysfunction rapidly modulates the abundance and thermal stability of cellular proteins

“…Protein homeostasis (proteostasis) depends not only on the abundance of each cellular protein but also on their specific folding, membrane topology, cellular location, and interaction partners and on diverse posttranslational modifications. An elaborate quality control system, also termed proteostasis network, regulates the synthesis, folding, transport, and degradation of proteins ( Sala et al, 2017 ; Hipp et al, 2019 ; Elsasser et al, 2022 Preprint ). It relies on molecular chaperones that facilitate and stabilize protein folding ( Hartl et al, 2011 ) and the ubiquitin–proteasome system (UPS) to recognize and remove damaged or surplus proteins ( Dikic, 2017 ).…”