The Proteasome and Autophagy

Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Integration of Clearance Mechanisms: The Proteasome and Autophagy Esther Wong and Ana Maria Cuervo Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461 Correspondence: [email protected] Cells maintain a healthy proteome through continuous evaluation of the quality of each of their proteins. Quality control requires the coordinated action of chaperones and proteolytic systems. Chaperones identifyabnormal or unstable conformations in proteins and often assist them to regain stability. However, if repair is not possible, the aberrant protein is eliminated from the cellular cytosol to prevent undesired interactions with other proteins or its organi- zation into toxic multimeric complexes. Autophagy and the ubiquitin/proteasome system mediate the complete degradation of abnormal protein products. In this article, we describe each of these proteolytic systems and their contribution to cellular quality control. We also comment on the cellular consequences resulting from the dysfunction of these systems in common human protein conformational disorders and provide an overview on current therapeutic interventions based on the modulation of the proteolytic systems. s described in previous articles on this sub- pathogenic proteins can all make the refolding Aject, cells count on a complex network of activity of chaperones insufficient to maintain molecular chaperones that assist proteins in proteome stability and prevent proteotoxicity folding and help stabilize the transient confor- (Morimoto 2008; Douglas et al. 2009; Koga mations that proteins adapt for trafficking et al. 2010). Under these conditions and for across membrane and during their assembly those proteins in which refolding is no longer and disassembly into functional complexes possible, cells count on proteolytic systems to (Large et al. 2009; Willis et al. 2009; Koga eliminate the unstable protein(s) and to recycle et al. 2010). However, different physiological their amino acids (Willis et al. 2009). The lyso- and pathological conditions may overwhelm somal system and the ubiquitin/proteasome the homeostatic capability of the chaperone system (UPS), the two main proteolytic systems network and favor protein aggregation. For in cells, along with the molecular chaperones, example, conditions resulting in massive pro- constitute essential components of the cellular tein unfolding such as acute oxidative stress or quality control systems (Ciechanover 2005). In heat shock, chronically proaggregating condi- this article, we briefly summarize the current tions that deplete cells of critical chaperones, knowledge regarding the molecular compo- and abnormal high levels of prone-to-aggregate nents of each of these proteolytic systems and Editors: Richard Morimoto, Jeffrey Kelly, and Dennis Selkoe Additional Perspectives on Protein Homeostasis available at www.cshperspectives.org Copyright # 2010 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a006734 Cite this article as Cold Spring Harb Perspect Biol 2010;2:a006734 1 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press E. Wong and A.M. Cuervo expand on recent evidence supporting the crit- in response to protein or organelle damage ical participation of both systems in the cellular and to replenish the intracellular reserve of free defense against proteotoxicity. We also describe amino acids that sustains protein synthesis recently established connections between mal- even in the absence of nutrients. Failure of the functioning of these proteolytic systems and the proteolytic systems to maintain basal cellular pathogenesis of common protein conforma- turnover or to accommodate to the degradative tional disorders with main emphasis on neuro- requirements of cells under stress conditions degenerative diseases. leads to altered cellular homeostasis, compro- mises the cellular energetic balance and often promotes intracellular accumulation of dam- INTRACELLULAR CLEARANCE aged components (Koga et al. 2010). Deposits MECHANISMS of conformationally altered proteins that or- Cells maintain a state of self-renewal, through ganize into insoluble oligomeric structures are the continuous synthesis and degradation of toxic for cells and lead to cell death in common all intracellular components, including soluble human pathologies generically known as pro- proteins and organelles (Ciechanover 2005). tein conformational disorders (Markossian Added to this regulated turnover, the activity of and Kurganov 2004; Morimoto 2008; Robinson the cellular degradative systems is up-regulated 2008) (Fig. 1). A Cytosol E Protein Lysosomes Unfolded Chaperone protein Ribosomes B Protein aggregate Chaperone Unfolded D protein Organelle C Chaperone Folded Proteasome Unfolded protein protein Figure 1. Coordinate action of chaperones and the proteolytic systems in quality control. Chaperones assist in the folding of de novo synthesized proteins (A), unfolding and refolding of proteins as they traffic into cellular compartments (B), and in the refolding of proteins when damaged by cellular aggressors (C). Proteins that fail to fold can be eliminated from the cell by two proteolytic systems: autophagy (D) and the ubiquitin/proteasome system (E). 2 Cite this article as Cold Spring Harb Perspect Biol 2010;2:a006734 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Cellular Clearance Mechanisms Two systems share the proteolytic cellular that become exposed as the substrate proteins load, the lysosomes and the UPS (Ciechanover unfold and undergo degradation. 2005). Although these two systems bear unique Intracellular degradation is often the most properties, there are a series of essential steps efficient mechanism to prevent toxicity associ- and components common to both of them ated with the accumulation of conformationally and required for their functions in cellular qual- altered proteins without affecting the cellular ity control. The common steps in protein degra- reserves of amino acids (Goldberg 2003; Mi- dation are: cargo selection and tagging, cargo zushima 2005). Cells can elicit alternative mech- recognition and delivery to the proteolytic ma- anisms when the load of proteins destined for chinery, degradation in the proteolytic core, degradation surpasses the activity of the proteo- and recycling of the constituent amino acids. Se- lytic systems or when there is a primary failure lection of cargo to be degraded is a prerequisite in the functions of these systems. For example, in both systems. Although for a long time it formation of large protein inclusions has been was generally accepted that cargo selection was proposed to be used by cells in certain instances only a prerequisite for the UPS and that de- to protect themselves from the toxic effect as- gradation in the lysosomal system was in-bulk sociated to oligomeric irreversible species of and occurred in a random manner, growing pathogenic proteins (Cohen and Dillin 2008). evidence support that this is not the case. In Secretion of the toxic protein products to the fact, as described more in detail in the follow- extracellular media is also used as a mechanism ing sections, molecular chaperones and other of cellular defense against proteotoxicity. Extra- cargo-recognition molecules are often the ones cellular proteases can take care of the secreted determining the fate of cellular proteins and products up to some extent, beyond which an- their degradation in one or the other proteo- titoxic aggregation mechanisms, similar to the lytic systems (Douglas et al. 2009). Degrada- ones described inside cells, result in the for- tion tags on the substrate proteins and the mation of protein inclusions or plaques in the machinery required for tagging can also be extracellular media. shared by both the proteolytic systems (Waters et al. 2009). Following tagging, the substrate AUTOPHAGY needs to be recognized by the proteolytic compartment. Association of different cargo recog- The degradation of intracellular components of nition molecules with the shared proteolytic any kind inside lysosomes is generically defined machinery, either the lysosomal compartment as autophagy, or self-eating (Mizushima et al. or the proteolytic core in the UPS, allows for 2008). The essential component of this proteo- variants inside each of the two proteolytic sys- lytic system are the lysosomes, single membrane tems dedicated for the degradation of partic- vesicles that contain in their lumen the larger ular subsets of proteins and organelles. Both variety of cellular hydrolases including pro- systems require catalytic activities capable of teases, lipases, glycosidases, and nucleotidases breaking the peptide bonds between amino (De Duve and Wattiaux 1966). Common to acids. Multiple proteases with different speci- these hydrolases is the fact that they all reach ficity constitute the proteolytic machinery of their higher enzymatic activity at the acidic pH the lysosomal system, whereas a single protease, of the lysosomal lumen. An ATP-dependent the 20S proteasome, bearing at least three differ- proton pump at the lysosomal membrane is re- ent proteolytic activities is responsible for pro- sponsible for the acidification of this organelle.

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