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Cellular Strategies of Protein Quality Control

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Cellular Strategies of Protein Quality Control Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Cellular Strategies of Protein Quality Control Bryan Chen, Marco Retzlaff, Thomas Roos, and Judith Frydman Department of Biology and BioX Program, Stanford University, Stanford, California 94305 Correspondence: [email protected] Eukaryotic cells must contend with a continuous stream of misfolded proteins that compro- mise the cellular protein homeostasis balance and jeopardize cell viability. An elaborate network of molecular chaperones and protein degradation factors continually monitor and maintain the integrity of the proteome. Cellular protein quality control relies on three distinct yet interconnected strategies whereby misfolded proteins can either be refolded, degraded, or delivered to distinct quality control compartments that sequester potentially harmful mis- folded species. Molecular chaperones play a critical role in determining the fate of misfolded proteins in the cell. Here, we discuss the spatial and temporal organization of cellular quality control strategies and their implications for human diseases linked to protein misfolding and aggregation. ROLE OF PROTEIN QUALITY CONTROL IN and can accumulate in potentially toxic protein CELLULAR INTEGRITY inclusions (Lansbury and Lashuel 2006). Pro- tein misfolding is emerging as a major mech- aintaining the integrity of the proteome is anism of human disease, as highlighted by Messential for cell viability. Although ener- the growing list of “conformational diseases,” getically favored, the native state of proteins is which result from the cellular accumulation of in a precarious equilibrium (Brockwell and misfolded proteins (Muchowski 2002; Saka- Radford 2007). Proteins often misfold during hira et al. 2002). These include a staggering the life of the cell, as a result of stochastic fluc- array of pathologies, ranging from lysosomal tuations, the presence of destabilizing muta- storage diseases (Sawkar et al. 2006), cancer tions, stress conditions, or unique metabolic (Dai et al. 2007), cystic fibrosis (Koulov et al. challenges, such as those occurring during can- 2010) to, most prominently, many neurodegen- cer or aging (Hartl and Hayer-Hartl 2009). In erative disorders such as Alzheimer (AD), Par- the cell, misfolded proteins can have deleterious kinson’s (PD), and Huntington’s (HD) diseases “gain-of-function” activities, in part because of (Caughey and Lansbury 2003; Cohen and Kelly their heightened tendency to aggregate (Dob- 2003; Morimoto 2008). It is becoming clear that son 2003). Although the precise mechanisms the cellular capacity to manage the proteome of toxicity are not well understood, it is clear declines during aging and this likely underlies that misfolded proteins engage in inappropriate the late onset of neurodegenerative diseases interactions with other cellular components caused by protein misfolding (Cuervo et al. Editors: Richard Morimoto, Jeffrey Kelly, and Dennis Selkoe Additional Perspectives on Protein Homeostasis available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a004374 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004374 1 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press B. Chen et al. 2005; Ben-Zvi et al. 2009; Demontis and Perri- aggregates, and regulate the inheritance of mon 2010). damaged and/or aggregation-prone species The cell has developed an elaborate machi- (Tyedmers et al. 2010a). Here we review the cen- nery that monitors and maintains the health tral mechanisms that maintain protein homeo- of its proteome (Frydman 2001; Hartl and stasis and quality control in eukaryotic cells and Hayer-Hartl 2009; Richter et al. 2010). Preserv- highlight the emerging concept that protein ing protein homeostasis, or “proteostasis,” quality control is associated with subcellular involves several parallel strategies that aim at compartments that sequester and concentrate either refolding, degrading, or sequestering both soluble and aggregated forms of misfolded misfolded polypeptides (Fig. 1) (Powers et al. proteins. 2009). Central to all these strategies is a network of molecular chaperones that recognizes mis- folded proteins (Hartl and Hayer-Hartl 2002; CAUSES AND CONSEQUENCES OF PROTEIN MISFOLDING McClellan et al. 2005a). Chaperones can actively promote refolding of the misfolded protein or, Under normal growth conditions, the cell con- if this is not possible, can promote their degra- tends with a continuous stream of misfolded dation via the ubiquitin-proteasome pathway proteins arising from inefficient protein bio- (McClellan et al. 2005b). Recent findings have genesis, expression of mutant proteins, excess revealed an additional cellular strategy to cope unassembled subunits of oligomeric complexes, with misfolded proteins that are not refolded and inefficiently translocated secretory and or degraded, namely sequestration into special- mitochondrial precursors (Balch et al. 2008; ized quality control compartments (Bagola and Voisine et al. 2010). The precise degree to which Sommer 2008; Kaganovich et al. 2008). The these processes burden the cellular quality con- spatial compartmentalization of cellular quality trol machinery has been a matter of controversy. control may help the cell cope with an overload In addition to these normal, physiological of aberrant proteins, prevent formation of toxic sources of misfolded proteins, a number of Re-Folding Degradation Chaperone Benefit Risk Benefit Risk • Protein is recovered • Chaperone overload • Recycles amino acids • Proteasome overload • Fast response • Misfolding/aggregation • Purges deleterious • Proteins not recovered assisted potential species Sequestration Benefit Risk • Bulk response that • Inclusions are quarantines toxic species difficult to clear • Mitigates burden on • May sequester proteostasis network non-specific proteins Figure 1. Cellular strategies to maintain protein homeostasis. Cells have evolved distinct yet interconnected cel- lular strategies to maintain protein homeostasis. Each strategy presents advantages and drawbacks. Misfolded proteins can either be refolded, degraded, or delivered to distinct quality control compartments that sequester potentially deleterious species. These strategies are all assisted by molecular chaperones that ensure the system remains balanced. Failure of the cellular strategies can tip the protein homeostasis balance and lead to a decrease in cell viability. 2 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004374 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Cellular Strategies of Protein Quality Control pathological conditions, environmental and Notably, enhancing chaperone expression via metabolic stresses, aging, and cancer, enhance hsf-1 and daf-16 delays aging and protects the production of misfolded proteins (Haigis organisms from neurodegenerative diseases and Yankner 2010). Altogether, these factors can (Morley and Morimoto 2004; Cohen et al. further tax the protein homeostasis machin- 2006). Little is known about the mechanisms ery. Potential environmental stresses include controlling misfolded protein sequestration, elevated temperature, exposure to chemicals thus it is unclear whether and how partitioning or heavy metals, viral/bacterial infections, and into cellular quality control compartments is tissue injury. Potential metabolic stresses are regulated. associated with nutrient balance, production of reactive oxygen species (ROS) and mitochon- drial dysregulation. These challenges are pre- CHAPERONES DICTATE THE BALANCE BETWEEN PROTEIN FOLDING, dominantly met by the activation of the DEGRADATION, AND AGGREGATION environmental stress response (ESR), which ele- vates expression of protective cellular compo- All aspects of cellular protein homeostasis nents (Voisine et al. 2010). Notably, the high depend on molecular chaperones (Frydman rates of cell division and high mutation rates 2001; Bukau et al. 2006; Schlecht et al. 2011). that accompany cancer lead to a higher load of Chaperones promote the folding of newly misfolded proteins (Whitesell and Lindquist synthesized polypeptides, their translocation 2005). Thus, cancer cells typically overexpress across membranes, and the refolding of stress- chaperones, and induction of an ESR is an inte- denatured substrates. Chaperones also play a gral part of carcinogenesis (Whitesell and Lind- key role in targeting misfolded proteins for deg- quist 2005). Conversely, aging is associated with radation as well as preventing aggregation. In a decline of protein homeostasis capacity (Mor- eukaryotic cells, these distinct functions are ley et al. 2002; Morley and Morimoto 2004). performed by two distinctly regulated chaper- Presumably, old cells or organisms accumulate one networks: the chaperones linked to protein deleterious mutations and oxidatively damaged synthesis (CLIPS), which are functionally and proteins, which overwhelm the capacity of the physically linked to the translation machinery protein homeostasis network (Gidalevitz et al. and assist folding of newly translated proteins 2006). This in turn promotes further protein (Albanese et al. 2006), and the heat shock pro- damage, eventually leading to widespread pro- teins (HSPs), which can be induced by HSF tein aggregation, toxicity, and cell
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