Protein homeostasis and aging: The importance of exquisite quality control - PubMed (original) (raw)

Review

Protein homeostasis and aging: The importance of exquisite quality control

Hiroshi Koga et al. Ageing Res Rev. 2011 Apr.

Abstract

All cells count on precise mechanisms that regulate protein homeostasis to maintain a stable and functional proteome. A progressive deterioration in the ability of cells to preserve the stability of their proteome occurs with age and contributes to the functional loss characteristic of old organisms. Molecular chaperones and the proteolytic systems are responsible for this cellular quality control by assuring continuous renewal of intracellular proteins. When protein damage occurs, such as during cellular stress, the coordinated action of these cellular surveillance systems allows detection and repair of the damaged structures or, in many instances, leads to the complete elimination of the altered proteins from inside cells. Dysfunction of the quality control mechanisms and intracellular accumulation of abnormal proteins in the form of protein inclusions and aggregates occur in almost all tissues of an aged organism. Preservation or enhancement of the activity of these surveillance systems until late in life improves their resistance to stress and is sufficient to slow down aging. In this work, we review recent advances on our understanding of the contribution of chaperones and proteolytic systems to the maintenance of cellular homeostasis, the cellular response to stress and ultimately to longevity.

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Figures

Figure 1. Cellular events that involve protein folding, refolding and degradation

Most cytosolic proteins fold spontaneously after synthesis, but those that fail to acquire a proper folded conformation are aided by chaperones and chaperonins which provide a favorable folding environment (1). Chaperones also assist folding of proteins synthesized in the endoplasmic reticulum (ER) (2). Further failure to fold will destine both cytosolic and ER luminal proteins for degradation (6). Unfolding of previously folded protein is required for their trafficking across membranes (3) and for their assembly into protein complexes. Chaperones also assist these proteins in their refolding after such events. Lastly, proteins can be targets for damaging agents (4 and 5) which lead to their unfolding and/or their aggregation. Chaperones will assist in refolding (4) or disaggregation (5). However, when the damage is irreversible molecular chaperones mediate the degradation of the altered proteins by the different proteolytic systems (6). Red flags indicate some steps altered with aging: 1. Reduced content of cytosolic chaperones; 2. Impaired ER response to stress; 3. Increased content of aggregated proteins; 4. Deficient targeting of damaged proteins toward degradation.

Figure 2. Schematic model of the ubiquitin/proteasome system

The main events that mediate targeting and degradation of soluble proteins by the proteasome are depicted here. 1. Most proteins are targeted for degradation through the covalent attachment of 4-5 ubiquitins through a lysine residue in their sequence. Ubiquitinization requires the coordinated action of catalytic enzymes (E1, E2 and E3) that act sequentially to activate the ubiquitin and ligate it to the substrate presented by the E3. 2. The proteolytic component, the proteasome or 26S, has a catalytic core (the 20S) formed by 4 rings containing two types of catalytic subunits (α and β), and a regulatory complex (the 19S). 3. Polyubiquitin chains are recognized by components of the regulatory subunit, where deubiquitinases reverse the covalent conjugation releasing free ubiquitin for recycling. The substrate is unfolded by unfoldases in the regulatory lid and ATPases in this complex provide the energy required for the injection of the substrate protein into the catalytic barrel or 20S proteasome. Red flags indicate described age-related changes in the different steps of this process: 1. Lower levels of catalytic and/or regulatory subunits and inefficient assembling of the 26S proteasome; 2. Reduced content/activity of free ubiquitin and conjugating enzymes; 3. Posttranslational modifications and crosslinking of the substrates can interfere with proteasome activity.

Figure 3. Intracellular autophagic pathways and changes with age

Three different mechanisms contribute to the delivery of cytosolic cargo to lysosomes: 1. macroautophagy, 2. microautophagy and 3. chaperone-mediated autophagy (CMA). Red flags indicate changes in the autophagic system with age: 1. Defects in the induction of macroautophagy; 2. Inefficient lysosomal clearance of the double membrane vesicles that sequester the cargo; 3. Decrease in the levels of the lysosomal receptor that mediates docking of CMA substrates at the lysosomal membrane and their translocation into the lumen.

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Protein homeostasis and aging: The importance of exquisite quality control - PubMed (original) (raw)