Proteolysis, the ubiquitin-proteasome system, and renal diseases - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:39 |只看该作者 |倒序浏览 |打印

作者：Richard Debigaré and S. Russ Price作者单位：Renal Division, Emory University, Atlanta, Georgia 30322


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      【摘要】
   Protein degradation is a critical process for the growth and function of cells. Proteolysis eliminates abnormal proteins, controls many cellular regulatory processes, and supplies amino acids for cellular remodeling. When substrates of proteolytic pathways are poorly recognized or there is mistiming of proteolysis, profound changes in cell function can occur. Based on these potential problems, it is not surprising that alterations in proteolytic enzymes/cofactors or in the structure of protein substrates that render them more or less susceptible to degradation are responsible for disorders associated with kidney cell malfunctions. Multiple pathways exist for protein degradation. The best-described proteolytic system is the ubiquitin-proteasome pathway, which requires ATP and degrades the bulk of cellular and some membrane proteins. This review will survey examples of renal abnormalities that are associated with defective protein degradation involving the ubiquitin-proteasome pathway. Loss of muscle mass associated with chronic renal failure, von Hippel-Lindau disease, Liddle syndrome, and ischemic acute renal failure will be discussed. These examples are indicative of the diverse roles of the ubiquitin-proteasome system in renal-associated pathological conditions. & i; \1 s$ J3 F  P, x
      【关键词】 protein degradation von HippelLindau disease Liddle syndrome ischemic acute renal failure muscle wasting. w5 N, M; y1 H8 }+ D
   INTRACELLULAR PROTEIN DEGRADATION is a tightly regulated process that is necessary to maintain normal cellular homeostasis. Cellular maintenance involves the elimination of abnormal proteins, control of regulatory processes, and the provision of amino acids for cellular remodeling. Under some circumstances, substrates of proteolytic pathways may be poorly recognized, or mistiming of proteolysis can lead to alterations in normal cellular functions. Based on these potential problems, it is not surprising that genetic alterations in proteolytic enzymes/cofactors or in the protein substrates that render them more or less susceptible to degradation are responsible for renal dysfunction or are a consequence of renal-associated disorders.

Multiple pathways exist for degrading proteins. Lysosomes contain proteases that have optimal activity at an acidic pH (e.g., cathepsins) and degrade membrane or endocytosed proteins. Traditionally, degradation by this pathway has been thought to be nonspecific, but there is growing evidence that some intracellular proteins can be specifically targeted to the lysososme for degradation ( 2, 13, 19 ). A second proteolytic pathway involves calcium-dependent proteases (e.g., calpains). These proteases are believed to play a role in cytoskeletal reorganization ( 68 ). A third intracellular proteolytic system is even more obscure and involves proteolysis that does not require energy. The specific enzymes that are involved and the mechanisms that regulate their activities are poorly understood, but this category may include metalloproteases and proteases involved in apoptosis. Finally, there are energy-requiring proteolytic systems. The best-described system is the ubiquitin-proteasome pathway, which requires ATP and degrades the bulk of cellular and some membrane proteins ( 54, 62 ).$ D4 T9 H/ D1 ]
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First, this review will depict the elements that constitute the ubiquitin-proteasome system and describe their functions in protein degradation. Second, selected renal diseases or conditions associated with renal dysfunction where protein degradation is abnormal will be discussed. Much of the information provided in this review was derived from an assortment of studies using renal and nonrenal cells and tissues. Whenever possible, studies involving kidney cells or animal models of renal diseases are used to highlight the role of the ubiquitin-proteasome system in physiological functions.( |% q. E' T4 K  f8 [* N

THE UBIQUITIN-PROTEASOME PATHWAY

The ubiquitin-proteasome system is complex and consists of a highly organized cascade of enzymatic reactions that select, mark, and degrade proteins ( Fig. 1 ) ( 20 ). Proteins destined for degradation by this system undergo the covalent attachment of a small protein, ubiquitin, to target protein degradation. Ubiquitin is abundantly expressed in all higher eukaryotic cells and is one of the most evolutionarily conserved proteins known. In most cases, ubiquitin is linked to the substrate protein through an isopeptide bond between the -amino group of lysines in the target protein and the COOH-terminal glycine of ubiquitin. Cycles of these reactions link additional ubiquitins to lysines within ubiquitins added previously. Typically, ubiquitin chains are linked through K48 in ubiquitin for proteosomal degradation, but alternate linkages through K11, K29, or K63 in ubiquitin have been described ( 76 ). Functions that may utilize these alternate linkages include DNA repair, quality control of protein folding in the endoplasmic reticulum, apoptosis, or regulation of the duration and intensity of signaling by effector molecules, notably tyrosine kinase-like growth factor receptors and the non-receptor tyrosine kinases of the Src family ( 63 ).
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Fig. 1. Ubiquitin-proteasome pathway. Initially, an ubiquitin-activating enzyme (E1) uses ATP to form an E1 ubiquitin thioester adduct with the COOH-terminal glycine of ubiquitin (Ub). After ubiquitin activation, members of the ubiquitin-carrier protein family (E2) participate in the transfer of the activated ubiquitin to protein substrates. In the majority of cases, a member of the ubiquitin protein ligase family (E3) also participates in the conjugation process. In a typical linkage, a series of ubiquitin molecules are conjugated to a substrate and a polyubiquitin chain is formed using Lys48 in ubiquitin as the site for chain extension. When a chain of 4 or more ubiquitin molecules is formed, the chain is recognized by the 26S proteasome and the substrate protein is degraded into short peptides. In some cases, polyubiquitin chains consisting of alternate linkages, ubiquitin molecules are conjugated to different lysine units in ubiquitin (K11, K29, K63), which will regulate different processes such as DNA repair, quality control of protein folding in the endoplasmic reticulum, apoptosis, or regulation of the duration and intensity of signaling by effector molecules./ n- @  ^" k  J4 ]
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The conjugation of ubiquitin to protein substrates involves a series of complex steps: initially, an E1 ubiquitin-activating enzyme uses ATP to form an E1 ubiquitin thioester adduct with the COOH-terminal glycine of ubiquitin ( Fig. 1 ). A single E1 enzyme is responsible for ubiquitin activation in all mammalian cells. After activation, members of the E2 ubiquitin-carrier protein family (also called ubiquitin-conjugating enzymes) participate in the transfer of the activated ubiquitin to protein substrates. In the vast majority of cases, a member of the E3 ubiquitin protein ligase family also participates in the conjugation process. The E3 ubiquitin ligases are a large class of a structurally diverse family of proteins that may number in the hundreds in humans ( 75 ). They provide selectivity to the ubiquitin process by serving as docking proteins that bring the substrate protein and the E2 carrier protein with activated ubiquitin together. In some instances, accessory proteins also interact with E3 ubiquitin ligases to facilitate substrate recognition (see RING Finger Ubiquitin Ligases ). Presently, E3 ubiquitin ligases are grouped into three major families based on structural similarities and the functional classes of substrates they recognize ( 52 ).) j8 R& O: J6 @6 A: J3 s( ?
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HECT Domain Ubiquitin Ligases
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These E3 ligases are referred to as the hect domain proteins because they have structural motifs that are homologous to the E6-AP COOH terminus. The biochemical action of HECT E3 ligase family members involves transfer of ubiquitin from the thioester linkage on E2 to a thioester linkage on E3, and then to a target protein. Substrate recognition features of the HECT ligases include a highly variable NH 2 -terminal domain and an internal WW domain that interact with a hydrophobic PPxY sequence (PY motif) in the target proteins. Most HECT E3 ligases also have an NH 2 -terminal C2 domain that mediates translocation to the plasma membrane in response to increases in intracellular Ca 2 . Examples of this enzyme subgroup are E6-AP, Nedd4, and Smurf1, which recognize and interact with the p53 tumor suppressor, the epithelial sodium channel (ENaC), and components of the TGF- -SMAD signal transduction pathway, respectively ( 3, 64, 83 ).9 a; d& Q0 `# O* `9 a+ H" r/ X

RING Finger Ubiquitin Ligases9 g# b# x7 ~5 v) D( Z( F  u
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The RING (for "Really Interesting New Gene") finger E3 ligases have a zinc-coordinating RING finger domain that includes eight metal-binding residues and enzymatic ligase activity responsible for the attachment of ubiquitin to the protein target. These E3 ligases can be grouped according to whether they are single-subunit E3s or form part of a multisubunit complex in which the RING finger subunit interacts with other proteins to provide substrate recognition ( Fig. 2 ).- l* j) m4 ]/ X( n4 P2 R+ n3 q' g

Fig. 2. RING (for "Really Interesting New Gene") domain ubiquitin ligases. c-Cbl is an example of a single-subunit RING finger protein, whereas von Hippel-Lindau (VHL) is an example of a multisubunit RING finger E3 complex. In the first case, the E3 ligase c-Cbl provides docking/recognition sites for both the substrate (e.g., growth factor receptors) and the ubiquitin-carrier protein (E2). In the second case, the E3 ligase VHL is composed of several subunits: cullin 2 (Cul2), RING box protein-1 (Rbx), elongin B and C (B, C), and von Hippel-Lindau protein (pVHL), an F-box protein. In this structure, the substrate binding/recognition site is provided by pVHL, whereas the ligase action is provided by Rbx through its RING-finger activity. Structural stability as well as E2 recognition are assumed by Cul2 and elongins.  G  z2 X" ~* S9 i) s5 h- E
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Single-subunit RING finger proteins include Mdm2, c-Cbl, and the inhibitors of apoptosis (IAPs). IAPs conjugate ubiquitin to other IAP molecules as well as to factors related to the induction of apoptosis, such as effector caspases. Ubiquitin conjugation to the p53 tumor suppressor and to some growth factor receptors is accomplished by Mdm2 and c-Cbl, respectively ( 16, 32, 71, 82 ). Another member of the RING finger E3 family is E3, which degrades protein substrates according to the "N-end rule." The N-end rule determines the rate of degradation of proteins based on their NH 2 -terminal residues. Selectivity is achieved because the E3 ligase recognizes proteins with "destabilizing" residues, defined as basic or bulky hydrophobic NH 2 -terminal amino acids. E3 ligase works in conjunction with the E2 14k ubiquitin-carrier protein to attach ubiquitin to the substrate proteins ( 4 ). Reports indicate that the N-end rule pathway participates in the ubiquitination of muscle proteins and that the system is activated in conditions associated with loss of muscle mass ( 38, 67 ).  ?4 s1 q$ C, e: o0 G8 |

Multisubunit RING finger E3 complexes are composed of proteins with distinct roles. A typical complex includes one of a variety of small RING finger proteins exhibiting E3 ligase activity and a member of the cullin family that interacts with linker proteins to recruit a substrate-recognition component to the complex. The substrate-recognition subunit is typically one of a family of variable F-box proteins ( 5 ). Examples of multisubunit E3 ligases include Skp1-cullin-F-box (SCF) complexes which make up the largest group of E3s. SCFs are responsible for the ubiquitination of -catenin and I B ( 25, 27, 36 ). The anaphase-promoting complex (also referred to as the cyclosome) adds ubiquitin to mitotic cyclins at specific times during the cell cycle. Changes in the phosphorylation of some anaphase-promoting complex subunits inactivate the E3 complex and provide cells with mechanisms to regulate the degradation of substrate proteins rapidly and specifically ( 70 ). A third example of a RING finger E3 complex is the von Hippel-Lindau (VHL) complex. VHL conjugates ubiquitin to hypoxia-inducible factor-1 (HIF-1) and will be discussed in more detail later ( 34, 63 ).3 ~' s) \( ?! k) @

U-Box Ligases
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Recently, E3 ligases have been identified that contain a unique domain designated as a U-box. This domain is similar to the RING finger, but it lacks canonical cysteine residues for zinc coordination. Only a few U-box proteins have been characterized, and little is known about their cellular functions ( 51 ).
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26S PROTEASOME
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The 26S proteasome is a large complex (2,000 kDa) that includes at least 50 subunits and exhibits multiple intrinsic protease activities to degrade proteins to small peptides. It is composed of a 20S catalytic core particle and two 19S regulatory particles. The 20S catalytic core is a barrel-shaped structure composed of four rings of seven subunits each. The outer rings consist of -class subunits, and the inner rings consist of -class subunits exhibiting at least three distinct proteolytic activities: 1 ) chymotrypsin like; 2 ) trypsin like; and 3 ) postacidic or caspase like (previously referred to as post-glutamylpeptidyl hydrolase like) because this activity preferentially cleaves proteins after aspartic residues ( 35 ). A multisubunit 19S particle is attached to each outer ring of the 20S core and functions as the recognition component of the 26S complex. Thus the 19S "cap" prevents proteins from being degraded in a random fashion. Models of proteolysis suggest that polyubiquitin chains of four or more residues on the target protein are recognized by subunits in the 19S particle; other subunits cleave the polyubiquitin chain for recycling. Target proteins are subsequently unfolded and guided into the 20S proteolytic core for cleavage to small peptides. The peptides are released from the proteasome and degraded into amino acids by exopeptidases in the cytosol. There are some exceptions when proteins are not completely degraded by the proteasome. Class I myosin heavy chain molecules are produced by a form of the proteasome that lacks the 19S cap particles. The 20S core particle is also modified by the substitution of several unique -subunits that alter the proteolytic activities of the complex. Peptides produced by this modified core are transported to the cell surface and are important for antigen presentation ( 8, 9, 62, 74 ).

DEUBIQUITINATING ENZYMES0 f$ M8 t! U% F2 s

The conjugation of ubiquitin to proteins is a reversible process that is tightly controlled at several levels. One level of regulation involves a large family of ubiquitin COOH-terminal hydrolases and ubiquitin-specific processing proteases (UBPs) that remove ubiquitin units attached to proteins. They cleave monoubiquitin from proteins and disassemble polyubiquitin chains that are released from substrates before degradation in the proteasome. Such actions allow recycling of ubiquitin for subsequent use in the conjugation reaction. They also prevent congestion of the proteasome due to the abnormal movement of targeted proteins to and through the proteasome. Deubiquitinating enzymes (DUBs) can also control the turnover of specific proteins by removing ubiquitin or polyubiquitin chains from the substrate, thus avoiding its degradation by the proteasome. Control of the turnover of a specific protein is important in a variety of cellular processes like transcriptional silencing, growth regulation, and even myogenesis ( 78 ). Recent studies suggest that numerous families of related DUBs are present in mammalian cells. Park et al. ( 50 ) demonstrated that muscle differentiation is antagonistically regulated by two UBPs, UBP45 and UBP65, that are encoded by one gene and arise by alternative splicing. Another family of DUBs, VDU1 and VDU2, was identified as VHL-interacting proteins based on yeast two-hybrid assays using a human kidney cDNA library (discussed in more detail later) ( 39, 40 ).
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RENAL-RELATED DISEASES INVOLVING THE UBIQUITIN-PROTEASOME SYSTEM. X- ]0 f# n$ i
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Protein degradation by the ubiquitin-proteasome pathway is a process that can be altered by genetic abnormalities that directly modify its activity, change the manner in which the system is regulated, or alter the structure of substrate proteins. Mechanisms that could lead to alterations in protein degradation by the ubiquitin-proteasome are listed below.7 Z: F: M* q% B7 L  \, a' f
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A mutation or deletion in a substrate protein (e.g., deletion of a polyubiquitin site) that leads to more or less degradation of the target protein% V( }2 `: L, i, E7 Y- K
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Mutations in the genes of pathway components that alter their level of expression; y3 K( k/ ~" b3 ^6 }3 i
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Interactions between transcription factors that alter the expression of pathway component proteins) H+ F5 M( Z1 E' A  E8 r

Presence of external stimuli (e.g., hormones, cytokines, hypoxia) that regulate the activity of the pathway directly or through initial steps, leading to degradation of a substrate protein
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Expression of an accessory factor that accelerates or suppresses the function of the pathway
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In some instances, the pathophysiological events observed in renal disease patients are a primary consequence of the defect. In other conditions, proteolysis of specific proteins is a secondary response to a primary abnormality or dysfunction. A few selected examples will be discussed in detail.

Muscle Wasting in Patients With Chronic Renal Failure and Other Catabolic Conditions
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Muscle atrophy is a serious complication for patients with chronic renal failure (CRF) because loss of protein mass is associated with excessive morbidity and mortality ( 28, 58 ). In CRF, a stimulus for muscle proteolysis is the metabolic acidosis that spontaneously occurs in patients with renal insufficiency ( 5a, 22 - 24, 59, 60 ). Hemodialysis may also accentuate muscle loss in CRF patients because the dialytic process increases whole body and muscle protein degradation ( 29 )./ {% R  F# c% o: {
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Studies of animals with various catabolic states (e.g., uremia, diabetes, sepsis, cancer, etc.) consistently show that loss of muscle mass results from increased degradation of muscle proteins by the ubiquitin-proteasome pathway ( 47 ). Muscle responses include increased levels of the mRNA-encoding components of the ubiquitin-proteasome pathway related to the N-end rule, such as the E2 14k carrier protein ( 79 ) and E3, the monomeric RING finger E3 ( 38 ). Two groups have identified new ubiquitin ligases that are expressed specifically and robustly in wasting muscles of animals with catabolic conditions. Muscle RING finger 1 (MuRF1) is a single-subunit RING finger E3 ligase ( 10 ). Atrophy gene-1 or atrogin-1 ( 21 ), also known as muscle atrophy F-box ( 10 ), is an F-box-containing protein that is a member of the SCF family of multisubunit E3 ubiquitin ligases. In 10-fold ( 21 ). The role of the muscle-specific E3s is unclear, but they do appear to be involved in muscle because mice deficient in MuRF1 or atrogin-1 exhibited a reduction in muscle atrophy in response to denervation ( 10 ). However, it is notable that the wasting was not completely prevented in the knockout mice, suggesting that multiple combinations of ubiquitin-conjugating enzymes (i.e., E2s and E3s) are involved in the muscle-wasting process., ]# L( o! X! G3 J. w

Several groups, including our own, have investigated the signals that are responsible for stimulating the ubiquitin-proteasome system in catabolic conditions. Metabolic acidosis, a low level of insulin, and cytokines have been implicated (reviewed in Refs. 26 and 37 ). In rats with metabolic acidosis, sepsis, starvation, or acute diabetes, the increase in protein degradation and ubiquitin-proteasome pathway mRNAs also requires glucocorticoids ( 18, 45, 46, 55, 80 ). We investigated the mechanism leading to increased levels of mRNA for the proteasome C3 subunit and ubiquitin (i.e., UbC ) genes in muscle of rats with chronic uremia ( 6 ) or acute diabetes ( 54 ) and found that transcription of these genes is increased. We then determined that glucocorticoids stimulate the transcription of the proteasome C3 subunit and ubiquitin UbC genes in L6 muscle cells by mechanisms involving two unexpected transcription factors, NF- B and Sp1, respectively ( 15, 44 ). In the case of the proteasome C3 subunit, NF- B acted as a suppressor to attenuate transcription and glucocorticoids blocked NF- B from binding to the C3 subunit promoter ( 15 ). In contrast, binding of Sp1 to the UbC promoter was increased by glucocorticoids ( 44 ). Studies are in progress to identify the signaling pathways that are involved in these transcriptional responses to glucocorticoids.

The VHL gene is located in chromosome region 3p25.5, and it encodes two active isoforms (24-30 and 18-20 kDa) that are tumor suppressors by genetic and functional criteria. Various mutations in the VHL protein (pVHL) cause the rare VHL disease, which displays an autosomal dominant pattern of inheritance. Patients with VHL syndrome (1/35,000 births) are predisposed to develop hemangioblastoma in several organs, including kidneys and renal cell carcinoma ( 81 ). In mammals, pVHL forms a stable, multimeric complex with elongin B and C, cullin 2, and RING box protein (Rbx)1. This complex is similar to the yeast Skp1-cdc53-Rbx1 protein complex that functions as a RING E3 ubiquitin ligase ( 33, 41 ). In the mammalian complex, pVHL functions as an F-box protein ( 48 ), whereas Rbx1 contains a RING finger-like motif related to ubiquitin ligase activity ( 33 ). The first confirmed substrate for the pVHL-E3 ligase complex is HIF-1, a heterodimeric transcription factor that is activated by hypoxia and rapidly degraded on reoxygenation. HIF-1 undergoes hydroxylation of two proline residues (Pro402 and Pro564) within an oxygen-dependent degradation domain ( 12, 34 ) by an oxygen-dependent prolyl-4-hydroxylase. VHL recognizes and interacts with the hydroxylated form of HIF-1 to facilitate the conjugation of ubiquitin to lysine residues in the oxygen-dependent degradation domain (reviewed in Ref. 77 ). HIF-1 is found in many cell types and regulates the expression of a variety of genes involved in metabolic adaptation, iron metabolism, angiogenesis, inflammation, and cell survival ( 77 ). Other substrates of the pVHL-E3 ligase complex include 1 ) hnRNP A2, a factor that participates in the posttranscriptional regulation of GLUT1 expression by a mechanism involving mRNA stabilization ( 53 ); and 2 ) activated PKC, an atypical PKC that plays a role in various cellular processes (e.g., proliferation, survival, establishment, and maintenance of cell polarity) ( 49 ). These substrates have been suggested to have a role in tumor development in organs where mutations in pVHL occur. Recently, two novel proteins named pVHL-interacting deubiquitinating enzyme-1 (VDU1) ( 39 ) and pVHL-interacting deubiquitinating enzyme-2 (VDU2) ( 39 ) were identified based on their interactions with pVHL in vitro and in vivo. VDU1 and VDU2 undergo VHL-dependent ubiquitination and are degraded by the proteasome. Like HIF-1, VDU1 and VDU2 interact with the -domain of pVHL, where most of the mutation in pVHL occurs. Because deubiquitinating enzymes can regulate the degradation of specific proteins by rescuing them from proteasome-mediated degradation (through the removal of ubiquitin chains), they also may play a role in the tumorigenesis of renal cells. Thus it is plausible that preservation of VDU1 and VDU2 due to defective pVHL-E3 ligase activity may rescue potential tumorigenic factors from ubiquitin-mediated degradation by the 26S proteasome.& b2 Z7 ?) k9 g8 S9 x$ Z

Liddle Syndrome
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Liddle syndrome is an autosomal-dominant form of hypertension characterized by early onset of severe hypertension, hypokalemia, metabolic alkalosis, salt sensitivity, and low values of serum aldosterone and renin. Mutations in subunits of ENaC lead to increased numbers of membrane channels and sustained channel activity ( 1, 11, 17, 65, 69 ). ENaC is composed of -, -, and -subunits that contain PY motifs recognized by WW domains in NEDD4, a member of the HECT E3 ubiquitin ligase family ( 42 ). Replacement of lysines clustered near the NH 2 termini of - and -ENaC proteins with arginine residues results in decreased conjugation of ubiquitin to the channel protein and increased ENaC channel activity ( 42 ). We also found that inhibition of the proteasome increases ENaC function in renal epithelial cells ( 43 ). These findings suggest that in patients with Liddle syndrome, mutations in PY motifs of the - and/or -subunits result in channels that do not interact with NEDD4, thus avoiding proteasomal degradation.

Hormones such as aldosterone also modulate ENaC expression on the cell surface. Aldosterone increases the expression of serum- and glucocorticoid-regulated kinase-1 (SGK1), which phosphorylates NEDD4 on serine residues and abolishes the interaction between NEDD4 and ENaC ( 14, 66 ). Thus defective regulation of ENaC expression by aldosterone and SGK1 may disturb Na homeostasis and contribute to the hypertensive state.# U) X: }) U. ~

Ischemic Acute Renal Failure2 S1 S6 I% T* J+ w8 z2 l

Acute renal failure (ARF) is mainly characterized by a sudden decline in renal function related to an impaired renal blood flow. The reduction in renal blood flow and the following reperfusion will lead to irreversible histopathological modifications in the kidneys. Over the last decade, loss of renal function owing to vascular compromise of the kidney has been widely recognized. Due to a lack of standardization in the operative definition of ARF, its incidence is difficult to evaluate. The literature reports a variation in incidence from 0.15 to 25% in all hospitalized and intensive care unit populations ( 56 ). Of those patients who survive after ARF, it is believed that 2-8% will need long-term dialysis support. ( 56 ). Although several hypotheses have been proposed to explain mechanisms of renal injury, the development of ischemic renal damage is still poorly understood. One hypothesis suggests that local production of endothelin-1 (ET-1), a strong vasoconstrictor, is a causative agent. After an ischemic event and subsequent reperfusion, local production of ET-1 persists for days after resolution of the ischemic injury ( 61 ). Recent studies of the pathogenesis of ischemic ARF in experimental animals have shown that administration of pharmacological inhibitors of the proteasome maintains renal function and attenuates the histological kidney degeneration that occurs in response to ischemia-reperfusion injury. Moreover, studies using a proteasome inhibitor (e.g., lactacystin) have shown that the increase in ET-1 normally seen after experimental ischemia-reperfusion is abolished, suggesting that a proteasome-dependent event has a role in the pathogenesis of ischemic ARF ( 30, 72, 73 ). There is evidence suggesting that the transcription factor NF- B stimulates ET-1 transcription ( 57 ). This is notable because NF- B activation requires the ubiquitin-proteasome system for degradation of the cytosolic inhibitor protein I B ( 31 ). Thus it is plausible that one protective effect of proteasome inhibitors is to block the induction of ET-1 transcription that occurs after ischemia-reperfusion injury.. f" {4 L3 O# l9 k3 d' _) O

CONCLUSION; j7 e" F. o2 x. j! B0 O

Cellular homeostasis requires that protein degradation be precisely regulated. To this end, the ATP-dependent, ubiquitin-proteasome system has evolved, and it is responsible for a sizable portion of the cellular proteolytic events. However, dysregulation of this system by several different mechanisms leads to inappropriate degradation of specific proteins and pathological consequences. As our knowledge of the ubiquitin-proteasome pathway and the proteins it degrades increases, it is likely that abnormal proteolysis via this pathway will be an important component of the pathogenesis of many renal diseases.+ X* F1 i  ?1 C0 U0 }

ACKNOWLEDGMENTS; Z5 g2 b4 s8 J! D2 x

We acknowledge support through National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-50740 and DK-63658 (to S. R. Price) and a Canadian Lung Association/Canadian Institutes of Health Research Fellowship Award (to R. Debigaré).

Address for reprint requests and other correspondence: S. R. Price, Renal Div., Rm. 338 Woodruff Memorial Bldg., 1639 Pierce Dr., Emory Univ., Atlanta, GA 30322 (E-mail: medrp{at}emory.edu ' u '@' d ' ).6 N+ I/ i' ]2 J. [5 t
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