Pathways of cellular proteostasis in aging and disease

Abstract

Ensuring cellular protein homeostasis, or proteostasis, requires precise control of protein synthesis, folding, conformational maintenance, and degradation. A complex and adaptive proteostasis network coordinates these processes with molecular chaperones of different classes and their regulators functioning as major players. This network serves to ensure that cells have the proteins they need while minimizing misfolding or aggregation events that are hallmarks of age-associated proteinopathies, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. It is now clear that the capacity of cells to maintain proteostasis undergoes a decline during aging, rendering the organism susceptible to these pathologies. Here we discuss the major proteostasis pathways in light of recent research suggesting that their age-dependent failure can both contribute to and result from disease. We consider different strategies to modulate proteostasis capacity, which may help develop urgently needed therapies for neurodegeneration and other age-dependent pathologies.

Figure 1.

The PN. (A) The flux of proteins through the PN relies on chaperones at many stages. PN capacity is sufficient to fold, often via intermediates, most newly synthesized polypeptides as they exit the ribosome. When a protein is no longer needed, it can be efficiently targeted for degradation either in the cytosol or nucleus via the UPS. Proteins that cannot be folded are also targeted for degradation via the UPS. During stress, the cell can increase PN capacity by activating a stress response. In aged or diseased cells, there is an increase in overall protein misfolding and aggregation, owing to increases in mutations and an overall decrease in PN capacity. These misfolded species may aggregate and/or be sequestered into large structures (aggresomes). A subset of misfolded species may form amyloid fibers that can further interfere with cellular processes. Chaperone factors that enhance particular steps are shown in green. Adapted from Hipp et al. (2014) and Kim et al. (2013). (B) Numbers for the major branches of the human PN, including synthesis, folding, and maintenance, and degradation branches, are shown. Datasets for generating these values were collected from the sources shown. The data were then arranged into nonoverlapping groups to represent the major PN branches. BAG, Bcl-2–associated athanogene; NAC, nascent chain-associated complex; RAC, ribosome-associated complex; RQC, ribosome quality control.

Figure 2.

Protein folding and aggregation. Nascent polypeptides fold by sampling various conformations and sequestering hydrophobic amino acid residues. Partially folded intermediates, both on- and off-pathway, can become trapped in localized energy minima. These species are at risk of aggregation by forming aberrant intermolecular contacts, which can lead to the formation of oligomers, amorphous aggregates, and amyloid fibrils. Molecular chaperones promote the formation of the native species by lowering free-energy barriers between kinetically stable intermediates, smoothing the protein folding landscape (green arrows), and preventing aberrant intermolecular interactions (red arrow). Adapted from Balchin et al. (2016), Hartl et al. (2011), and Kim et al. (2013).

Figure 3.

Proteome complexity increases from prokaryotes to eukaryotes. (A) The average protein length (in number of amino acids) and total number of chaperones in the proteomes of bacteria (Escherichia coli), yeast (Saccharomyces cerevisiae), and humans (Homo sapiens) are shown. The increase in proteome complexity with increasing organismal complexity, from prokaryotes to eukaryotes, and from single-cell to multicellular organisms is accompanied by an increase in chaperone number. Comparative chaperomes were generated by UniProtKB queries by using identical keyword searches for chaperones for each organism. Differences between the total human chaperome number and previously reported numbers (Brehme et al., 2014; Fig. 1 B) arise from a more-stringent definition here to ensure appropriate comparisons between organisms. (B) The numbers of members of each of the major chaperone classes are shown for different organisms with selective cochaperones shown for comparison (Genevaux et al., 2007; Vos et al., 2008; Brehme et al., 2014; Rizzolo et al., 2017). Protein folding in the bacterial (C) and eukaryotic (D) cytosol. Most proteins use folding assistance on exit from the ribosome. Ribosome-associated factors include Trigger factor in bacteria and the nascent chain-associated complex (NAC) and ribosome-associated complex (RAC) in eukaryotes. Downstream Hsp70s (DnaK in bacteria) work with their cofactors Hsp40 (DnaJ in bacteria) and nucleotide exchange factors (NEFs; GrpE in bacteria) in protein folding. Some proteins must be transferred to the chaperonin class of chaperones for further folding (GroEL/ES in bacteria and TRiC in eukaryotes). In eukaryotes, prefoldin can transfer some substrates directly to TRiC. Cofactors such as Hop (Hsp70-Hsp90 organizing protein) can mediate interactions with Hsp90 (HtpG in bacteria), which also acts downstream of Hsp70 in the folding of a subset of proteins mainly engaged in cell signaling. Adapted from Balchin et al. (2016).

Figure 4.

Healthy and aged proteostasis. (Left) The PN ensures that most proteins fold to a stable native state. When these proteins are no longer needed or errors in folding occur, they are efficiently targeted for degradation, primarily via the UPS. On transient stress (middle), otherwise healthy cells activate a stress response. Chaperone sensors bind to misfolded species and trigger the appropriate transcriptional program leading to a general increase in protein-folding capacity, increase in protein turnover, and decrease in the production of additional substrates via attenuation of general protein translation. In cases of chronic stress, such as during disease or aging (right), sequestration of key PN components by aggregates can lead to aberrant transcriptional programs, a deficit in folding capacity due to a lack of functionally available chaperones, and a buildup of misfolded species due to a decline in proteasomal capacity. This can lead to a chronic inability to restore PN balance and further accumulation of misfolded species.