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Protein Degradation by the Ubiquitin–Proteasome Pathway in Normal and Disease States

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Protein Degradation by the Ubiquitin–Proteasome Pathway in Normal and Disease States Review Protein Degradation by the Ubiquitin–Proteasome Pathway in Normal and Disease States Stewart H. Lecker,* Alfred L. Goldberg,† and William E. Mitch‡ *Nephrology Division, Beth Israel Deaconess, and †Department of Cell Biology, Harvard Medical School, Boston, Massachusetts; and ‡Nephrology Division, Baylor College of Medicine, Houston, Texas J Am Soc Nephrol 17: 1807–1819, 2006. doi: 10.1681/ASN.2006010083 ll intracellular proteins and many extracellular pro- after aspartic acid residues. These enzymes, which are cysteine teins are continually “turning over;” i.e., they are proteases, are critical in destruction of cell constituents during A being hydrolyzed to their constituent amino acids apoptosis (7). and replaced by new synthesis. Although the continual de- struction of cell proteins might seem wasteful, this process Ubiquitin Proteasome Pathway serves several important homeostatic functions. Individual pro- During the past two decades, the UPP has taken center stage teins in the nucleus and cytosol, as well as in the endoplasmic in our understanding of the control of protein turnover (Figure reticulum (ER) and mitochondria, are degraded at widely dif- 1). The UPP consists of concerted actions of enzymes that link fering rates that vary from minutes for some regulatory en- chains of the polypeptide co-factor, Ub, onto proteins to mark zymes to days or weeks for proteins such as actin and myosin them for degradation (8,9). This tagging process leads to their in skeletal muscle or months for hemoglobin in the red cell. recognition by the 26S proteasome, a very large multicatalytic Cells contain multiple proteolytic systems to carry out the protease complex that degrades ubiquitinated proteins to small degradation process and complex regulatory mechanisms to peptides (10). Three enzymatic components are required to link ensure that the continual proteolytic processes are highly selec- chains of Ub onto proteins that are destined for degradation. E1 tive. Therefore, excessive breakdown of cell constituents is (Ub-activating enzyme) and E2s (Ub-carrier or conjugating pro- prevented. Overall, the rates of protein synthesis and degrada- teins) prepare Ub for conjugation, but the key enzyme in the tion in each cell must be balanced precisely because even a process is the E3 (Ub-protein ligase), because it recognizes a small decrease in synthesis or a small acceleration of degrada- specific protein substrate and catalyzes the transfer of activated tion, if sustained, can result in a marked loss of mass in the Ub to it (Figure 2). The discovery of Ub and the biochemistry of organism (1). its conjugation to substrate proteins culminated in the award- In all tissues, the majority of intracellular proteins are de- ing of the Nobel Prize in Chemistry in 2004 to Avram Hershko, graded by the ubiquitin (Ub)–proteasome pathway (UPP) (2). Aaron Ciechanover, and Irwin Rose (http://nobelprize.org/ However, extracellular proteins and some cell surface proteins chemistry/laureates/2004/). are taken up by endocytosis and degraded within lysosomes. Since the initial description of the UPP as a protein tagging These organelles contain several acid-optimal proteases, in- and destruction mechanism, knowledge in this area has ex- cluding cathepsins B, H, and D, and many other acid hydro- ploded, with thousands of proteins shown to be degraded by lases. Some cytosolic proteins are degraded in lysosomes after the system and additional novel functions for Ub conjugation being engulfed in autophagic vacuoles that fuse with lysosomes being uncovered. The major functions of the pathway are de- (3,4). In most cells, this process is accelerated by the lack of scribed next. insulin or essential amino acids and in liver by glucagon (5). There are other cytosolic proteolytic systems in mammalian ϩ Rapid Removal of Proteins cells. The Ca2 -activated (ATP-independent) proteolytic pro- Unlike most regulatory mechanisms, protein degradation is cess involves the cysteine proteases termed calpains. These inherently irreversible. Destruction of a protein can lead to a proteases seem to be activated when cells are injured and ϩ complete, rapid, and sustained termination of the process in- cytosolic Ca2 rises, so they may play an important role in volving the protein as well as a change in cell composition. The tissue injury, necrosis, and autolysis (6). Another important rapid degradation of specific proteins permits adaptation to family of cytosolic proteases is the caspases that cleave proteins new physiologic conditions. Received January 26, 2006. Accepted April 13, 2006. Regulation of Gene Transcription Published online ahead of print. Publication date available at www.jasn.org. Ub conjugation affects transcription by multiple mechanisms (11). Many transcription factors are ubiquitinated and de- Address correspondence to: Dr. William E. Mitch, Nephrology Division M/S: BCM 285, Baylor College of Medicine, One Baylor Plaza, Alkek N-520, Houston, graded by the proteasome. In fact, in many cases, transcrip- TX 77030. Phone: 713-798-8350; Fax: 713-798-5010; E-mail: [email protected] tional activation domains and signals for Ub conjugation di- Copyright © 2006 by the American Society of Nephrology ISSN: 1046-6673/1707-1807 1808 Journal of the American Society of Nephrology J Am Soc Nephrol 17: 1807–1819, 2006 Figure 1. The ubiquitin (Ub)-proteasome pathway (UPP) of protein degradation. Ub is conjugated to proteins that are des- tined for degradation by an ATP-dependent process that in- volves three enzymes. A chain of five Ub molecules attached to the protein substrate is sufficient for the complex to be recog- nized by the 26S proteasome. In addition to ATP-dependent reactions, Ub is removed and the protein is linearized and injected into the central core of the proteasome, where it is digested to peptides. The peptides are degraded to amino acids Figure 2. The three biochemical steps that conjugate Ub to the by peptidases in the cytoplasm or used in antigen presentation. protein substrate. The ATP-dependent process is repeated until Illustration by Josh Gramling—Gramling Medical Illustration. a chain of Ub molecules is attached. Illustration by Josh Gram- ling—Gramling Medical Illustration. rectly overlap. Ubiquitination and proteolysis of activators even may stimulate transcriptional activity by removing “spent” activators and resetting a promoter for further rounds membrane–associated Ub conjugating proteins; these then are of transcription (12). In addition, transcription factors can be targeted to cytosolic proteasomes (16). regulated by changes in their location. For example, NF-␬B, the proinflammatory transcriptional activator, is kept outside the Functioning of the Immune System nucleus by its interaction with I␬B. I␬B degradation is triggered Antigen presentation on MHC class I molecules is dependent by its phosphorylation, which causes it to be recognized by the on proteasomal function (see section titled The Proteasome and E3 ␤-transducin repeat containing protein (␤-TRCP). I␬B then is Immune Surveillance) (2). ubiquitinated and rapidly degraded, and the freed NF-␬B translocates to the nucleus. This step is critical in acceleration of the inflammatory response (13). As a Source of Amino Acids In states of inadequate caloric intake or with catabolic dis- Quality Control Mechanism eases, the overall breakdown of cell proteins, especially in The UPP selectively eliminates abnormally folded or dam- skeletal muscle, increases to provide the organism with amino aged proteins that have arisen by missense or nonsense muta- acids that are used in gluconeogenesis, new protein synthesis, tions, biosynthetic errors, or damage by oxygen radicals or by and energy production. Activation of this process in fasting or denaturation (especially at high temperatures). In cystic fibro- disease can lead to muscle atrophy (see section titled Mecha- sis, the mutant form of the transmembrane conductance regu- nisms that Cause Loss of Muscle Protein in Uremia). lator protein (CFTR) is selectively degraded and therefore fails to reach the cell surface (14,15). Because the Ub conjugation and degradation machinery are cytoplasmic, the destruction of Other Functions of Ub Not Associated with Proteolysis CFTR demonstrates that the UPP degrades misfolded or se- Ub also can be conjugated to proteins as a monomer (rather creted proteins. In the process of ER-associated degradation, than as a typical Ub chain). This type of tagging triggers inter- many misfolded proteins within the ER are retrotranslocated nalization of cell surface proteins into the endocytic pathway out of that compartment into the cytosol by a series of ER (17) and also can be used in the regulation of transcription (18). J Am Soc Nephrol 17: 1807–1819, 2006 Protein Degradation by the Ubiquitin-Proteasome Pathway 1809 Ub Is Linked to Substrates through an channel for internalization and degradation (27) by recognizing Enzymatic Cascade specific residues in the channel’s cytoplasmic tails. When these Ub is composed of 76 amino acids. Its C-terminus is a critical proteins cannot interact, either as a result of mutations in the glycine that is required for its conjugation to other Ub mole- sodium channel or the E3, the channel is more stable, resulting cules and substrates, and it contains internal lysine residues in increased sodium reabsorption, hypervolemia metabolic al- that are used in the creation of polyubiquitin chains. Ub is not kalosis, and hypertension, a genetic defect known as Liddle’s expressed directly
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