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Review
. 2017 Mar 1;9(3):a023523.
doi: 10.1101/cshperspect.a023523.

Protein Quality Control in Health and Disease

Tatyana Dubnikov  1 , Tziona Ben-Gedalya  1 , Ehud Cohen  1
Affiliations
Review

Protein Quality Control in Health and Disease

Tatyana Dubnikov et al. Cold Spring Harb Perspect Biol. .

Abstract

Maintaining functional protein homeostasis (proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP). We also describe how protein quality control is integrated at the organismal level and discuss future perspectives on utilizing proteostasis maintenance as a strategy to develop novel therapies for the treatment of proteinopathies.

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Figures

Figure 1.
Figure 1.
Folding and quality control of nascent prion protein (PrP) molecules. As a secreted protein, PrP bears an endoplasmic reticulum (ER)-localization signal (red) that mediates its cotranslational translocation into the ER (I). A fraction of the nascent PrP molecules stays cytosolic and is designated for degradation by the ubiquitin-proteasome system (II). In the ER, the localization signal is cleaved (III), and a glycosylphosphatidylinositol (GPI) anchor and glycans are attached to the protein (IV). Next, the molecule undergoes a series of chaperone-assisted folding events that involve the formation of a single cysteine–cysteine bridge, cis–trans isomerization by cyclophilin B, and calnexin/calreticulin-assisted folding (V). Successfully folded molecules (VI) are transported to the Golgi apparatus (VII) for further processing, whereas molecules that failed to fold properly are directed for degradation by the ER-associated degradation mechanism (VIII). After additional maturation steps at the Golgi apparatus (IX), mature PrP molecules are shuttled to the cell surface (X), where they are presented on membrane rafts (XI). SP, Signal peptide.
Figure 2.
Figure 2.
Cellular unfolded protein response mechanisms. The accumulation of misfolded proteins activates organelle-specific complex mechanisms that modulate gene expression in an attempt to restore proteostasis. Upon accumulation of misfolded proteins within the cytosol, heat-shock factor 1 (HSF-1) trimerizes, enters the nucleus, and activates the expression of various genes, including the subset of chaperones of the heat-shock protein group. Protein misfolding in the mitochondria activates the mitochondrial unfolded protein response (UPRmt), which activates the expression of genes that encode for mitochondrial chaperones. This expression is promoted by transcription factors such as CHOP. Similarly, at least three signaling cascades can respond to the accrual of unfolded proteins within the ER. The ER unfolded protein response (UPRER) mechanisms are based on the sensing of folding stress membrane proteins (ATF, IRE1, and PERK), the migration of transcription factors into the nucleus (such as ATF6[N] and XBP1), and the induction of chaperone-encoding genes. Lysosomes also signal to activate gene expression in the nucleus of Caenorhabditis elegans. The lysosomal acid lipase LIPL-4 signals to confer the nuclear localization of the lipid chaperone LBP-8, which induces gene expression. This pathway was shown to promote longevity; however, its possible roles in the maintenance of protein quality control are yet to be explored.
Figure 3.
Figure 3.
Aggregated proteins are deposited in cellular sites. (A) The overwhelming of protein quality-control mechanisms by massively overexpressing certain aggregation-prone proteins, proteasome inhibition, or the impairment of chaperone activity leads to the deposition of aggregated proteins in juxtanuclear inclusion bodies known as aggresomes. Aggresomes are confined by collapsed vimentin fibers, co-localize with the microtubule-organizing center (MTOC), attract chaperones and proteasomes, and serve as protein quality-control centers. (B) The juxtanuclear quality control compartment (JUNQ) shares key features with the aggresome. It localizes next to the nucleus, possibly associated with the MTOC, and serves as a dynamic inclusion body. Lipid droplets (LDs) are found in close proximity with the JUNQ of yeast that overexpress aggregation-prone proteins. LDs secrete sterols that assist in clearing protein aggregates. (C) Terminally aggregated proteins accumulate in an insoluble protein deposit (IPOD). Proteins within the IPOD exhibit a low rate of molecular exchange with the cytosol and are highly immobile. (D) Under certain circumstances, proteins that aggregate within the ER are deposited in the ER-derived quality-control compartment (ERQC), which can serve as a platform for proteasome-mediated protein degradation.
Figure 4.
Figure 4.
The regulation of proteostasis at the organismal level. Studies in nematodes unveiled that the proteostasis of somatic tissues is regulated by neuron-dependent and -independent manners. Thermosensory neurons (AFD) activate the heat-shock response (HSR) in the intestine upon exposure to heat (I). Serotonin and chemosensory neurons are involved in this activation. The HSR-coordinating, interneuronal communication mechanisms are largely unexplored. Neurons were also found to control the activity of the endoplasmic reticulum unfolded protein response (UPRER) (II) and mitochondrial unfolded protein response (UPRmt) (III) in distal tissues. Intestine and muscle cells exchange signals to activate the chaperone Hsp90 (DAF-21 in the nematode) when metastable proteins fail to fold properly (IV). Signals from germ cells regulate proteostasis in muscle cells (V).
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