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Reviews |
* Nephrology Division, Beth Israel Deaconess; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts; and Nephrology Division, Baylor College of Medicine, Houston, Texas
Address correspondence to: Dr. William E. Mitch, Nephrology Division M/S: BCM 285, Baylor College of Medicine, One Baylor Plaza, Alkek N-520, Houston, TX 77030. Phone: 713-798-8350; Fax: 713-798-5010; E-mail: mitch{at}bcm.edu
Received for publication January 26, 2006. Accepted for publication April 13, 2006.
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Introduction |
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In all tissues, the majority of intracellular proteins are degraded by the ubiquitin (Ub)–proteasome pathway (UPP) (2). However, extracellular proteins and some cell surface proteins are taken up by endocytosis and degraded within lysosomes. These organelles contain several acid-optimal proteases, including cathepsins B, H, and D, and many other acid hydrolases. Some cytosolic proteins are degraded in lysosomes after being engulfed in autophagic vacuoles that fuse with lysosomes (3,4). In most cells, this process is accelerated by the lack of insulin or essential amino acids and in liver by glucagon (5). There are other cytosolic proteolytic systems in mammalian cells. The Ca2+-activated (ATP-independent) proteolytic process involves the cysteine proteases termed calpains. These proteases seem to be activated when cells are injured and cytosolic Ca2+ rises, so they may play an important role in tissue injury, necrosis, and autolysis (6). Another important family of cytosolic proteases is the caspases that cleave proteins after aspartic acid residues. These enzymes, which are cysteine proteases, are critical in destruction of cell constituents during apoptosis (7).
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Ubiquitin Proteasome Pathway |
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Rapid Removal of Proteins
Unlike most regulatory mechanisms, protein degradation is inherently irreversible. Destruction of a protein can lead to a complete, rapid, and sustained termination of the process involving the protein as well as a change in cell composition. The rapid degradation of specific proteins permits adaptation to new physiologic conditions.
Regulation of Gene Transcription
Ub conjugation affects transcription by multiple mechanisms (11). Many transcription factors are ubiquitinated and degraded by the proteasome. In fact, in many cases, transcriptional activation domains and signals for Ub conjugation directly overlap. Ubiquitination and proteolysis of activators even may stimulate transcriptional activity by removing "spent" activators and resetting a promoter for further rounds of transcription (12). In addition, transcription factors can be regulated by changes in their location. For example, NF-
B, the proinflammatory transcriptional activator, is kept outside the nucleus by its interaction with IB. IB degradation is triggered by its phosphorylation, which causes it to be recognized by the E3 
-transducin repeat containing protein (-TRCP). IB then is ubiquitinated and rapidly degraded, and the freed NF-B translocates to the nucleus. This step is critical in acceleration of the inflammatory response (13).
Quality Control Mechanism
The UPP selectively eliminates abnormally folded or damaged proteins that have arisen by missense or nonsense mutations, biosynthetic errors, or damage by oxygen radicals or by denaturation (especially at high temperatures). In cystic fibrosis, the mutant form of the transmembrane conductance regulator 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 CFTR demonstrates that the UPP degrades misfolded or secreted proteins. In the process of ER-associated degradation, many misfolded proteins within the ER are retrotranslocated out of that compartment into the cytosol by a series of ER membrane–associated Ub conjugating proteins; these then are targeted to cytosolic proteasomes (16).
Functioning of the Immune System
Antigen presentation on MHC class I molecules is dependent on proteasomal function (see section titled The Proteasome and Immune Surveillance) (2).
As a Source of Amino Acids
In states of inadequate caloric intake or with catabolic diseases, the overall breakdown of cell proteins, especially in skeletal muscle, increases to provide the organism with amino acids that are used in gluconeogenesis, new protein synthesis, and energy production. Activation of this process in fasting or disease can lead to muscle atrophy (see section titled Mechanisms that Cause Loss of Muscle Protein in Uremia).
Other Functions of Ub Not Associated with Proteolysis
Ub also can be conjugated to proteins as a monomer (rather than as a typical Ub chain). This type of tagging triggers internalization of cell surface proteins into the endocytic pathway (17) and also can be used in the regulation of transcription (18).
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Ub Is Linked to Substrates through an Enzymatic Cascade |
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The initial step in conjugation of Ub onto proteins is activation of Ub at its C-terminus by the Ub-activating enzyme E1 (Figure 2). This abundant 110-kD enzyme uses ATP to generate a Ub thiolester, a highly reactive form of Ub (19). In mammalian organisms, a single, functional E1 enzyme has been found, unlike the large number of E2s and E3s in cells (20). Once activated, the Ub that is bound to E1 via the thiolester linkage is transferred to a sulfhydryl group of one of the 30 to 40 Ub carrier proteins or E2s (21). The E2s generally are small proteins that share a conserved 16-kD core that contains the cysteine that forms a thiolester linkage with the activated Ub (21). The large number of E2s helps to generate the specificity of the ubiquitination system, because specific E2s function in the degradation of various types of substrates, and they can conjugate with various E3s.
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E3s Recognize the Cellular Proteins That Undergo Ub Conjugation |
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HECT domain proteins are large monomeric E3s that consist of two functionally distinct domains (23). The C-terminal HECT domain (350 amino acids) accepts the activated Ub from the E2s by forming a thiolester linkage with Ub, enabling it to be transferred to the substrate. HECT-domain E3s directly bind activated Ub and are actual components of the enzymatic conjugation cascade (24). The prototypical member of this family is the E6-associated protein (E6-AP) (25). Lack of this enzyme causes Angelman’s syndrome, an inherited neurologic disorder (26). Nedd4, another HECT-E3, targets the epithelial sodium channel for internalization and degradation (27) by recognizing specific residues in the channel’s cytoplasmic tails. When these proteins cannot interact, either as a result of mutations in the sodium channel or the E3, the channel is more stable, resulting in increased sodium reabsorption, hypervolemia metabolic alkalosis, and hypertension, a genetic defect known as Liddle’s syndrome (28).
The vast majority of E3s contain RING finger domains. These 40- to 60-residue zinc-binding motifs contain core amino acids, cysteine, and histidine (22,29). RING finger E3s can be monomeric enzymes or multisubunit complexes. As a whole, they seem to serve as scaffolds that bring the substrate and the E2 into close proximity, an optimal condition for Ub conjugation (29–31). Monomeric RING finger E3s include the oncoprotein Mdm2, a physiologic regulator of p53 stability in normal cells (32), and c-Cbl, which catalyzes ubiquitination of certain cell surface receptors. Two E3s that are important in the processes of muscle atrophy, muscle ring finger-1 (MuRF-1), and E3
belong to this group; E3 was among the first of the E3s to be biochemically identified. It recognizes protein substrates on the basis of their N-terminal amino acid. Proteins that begin with large basic or hydrophobic residues are targeted for ubiquitination and degradation by E3 (32a). This "N-end rule" pathway seems to be important in the destruction of cohesions (33), certain signaling molecules (e.g., regulator of G-protein signaling 4 [RGS4] [34]), and the enhanced protein degradation that occurs in atrophying muscle (see section titled Mechanisms That Cause Loss of Muscle Protein in Uremia).
Other RING-finger E3s contain many subunits that serve as scaffolds to bring together the substrate and an E2 conjugated to an activated Ub. The largest (1.5 MDa), most complex E3 is the anaphase-promoting complex. It is important in ubiquitination of mitotic cyclins and other proteins that are involved in cell-cycle control. Cullin-RING Ub ligases form the largest group of E3s (29). The basic core of these E3s is the elongated, rigid cullin subunit. On end of these subunits bind the RING component (typically Rbx1/Roc1) and the E2, whereas at the other end, the substrate-interacting protein is bound, often through an additional adaptor protein. Because of the large number of cullins and substrate-binding subunits, the same organization using the same basic mechanism can recognize and ubiquitinate a large number of diverse proteins.
The best understood group of cullin-RING ligases are the Skp1–Cul1–F-box (SCF) complexes. The F-box protein is the subunit that contains the substrate-binding motif (see below). It binds to an adaptor, Skp1, through an approximately 45–amino acid F-box motif. Substrates of SCF complexes E3s are many key molecules that control inflammation and cell growth (e.g., IB, NF-B, -catenin) and cell cycle–induced proteins (e.g., the cyclin-dependent kinase inhibitor p27Kip1). In many cases, phosphorylation leads to binding of substrate to the F-box subunit and subsequent Ub conjugation. Regulated expression of F-box proteins can cause tissue- and disease-specific Ub conjugation of target proteins. For example, the F-box protein atrogin-1/MAFbx is expressed at high levels specifically in atrophying skeletal and cardiac muscle (35).
In addition to phosphorylation, other types of posttranslational protein modifications can stimulate ubiquitination. For example, cellular oxygen levels are sensed by the Von Hippel-Lindau (VHL)-containing VHL-elongin BC (VBC) E3, which recognizes hydroxyproline (an oxygen-dependent protein modification). When oxygen levels are adequate in cells, the hypoxia-inducible factor 1 (HIF-1) transcriptional activator undergoes prolyl hydroxylation and ubiquitination by this E3. When oxygen pressure falls, the unmodified HIF-1 is not recognized by VHL and is not degraded, so it triggers transcription of genes for angiogenesis (vascular endothelial growth factor, erythropoietin, and glycolytic enzymes [36]). The VBC complex is another cullin-RING ligase, made up of Cul2 and a substrate-interacting domain that is made up of VHL and the adaptors elonginB and elonginC. VHL mutations are associated with highly vascular tumors in the kidney, presumably as a result at least in part of the presence of stable, active HIF-1. Other protein modifications that have been shown to recruit E3s include glycosylation, nitrosylation, and deacetylation. Substrate modification adds another layer of regulation to the UPP by integrating cell signaling and metabolic pathways with the conjugation-degradation machinery.
Recently, a novel group of enzymes with Ub ligase activity have been identified: The U-box domain proteins, such as Ub fusion degradation protein 2 (UFD2) and C-terminal of Hsp-70-interacting protein (CHIP). These E3 enzymes contain atypical RING finger motifs (37). CHIP is important for the removal of abnormal proteins such as the misfolded CFTR in cystic fibrosis and tau protein of polyglutamine repeat proteins that are present in several neurodegenerative diseases (38). Degradation of these proteins begins when they are bound by specific molecular chaperones followed by binding of the E3s. This leads to selective ubiquitination of the chaperone-bound substrate.
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Most Cell Proteins Are Degraded by the 26S Proteasome |
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rings are identical, as are the two inner rings. Three of the subunits in the rings contain the proteolytic active sites that are positioned on the interior face of the cylinder. The outer subunits of the 20S particle surround a narrow, central, and gated pore through which substrates enter and products exit (41). Substrate entry is a complex process that is catalyzed by the 19S particle. This complex architecture evolved to isolate proteolysis within a nano-sized compartment and prevents the nonspecific destruction of cell proteins. One can view protein ubiquitination and the functioning of the 19S particle as mechanisms that ensure proteolysis as an exquisitely selective process; only certain molecules get degraded within the 20S proteasome (42).
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The Proteasome’s Multistep Mechanism |
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After the substrate enters the 20S’s central chamber, the polypeptide is cleaved by its six proteolytic sites on the inner face of the changer, forming small peptides that range from three to 25 residues in length (47). Unlike traditional proteases, which cut a protein once and release the fragments, the proteasome digests the substrates all the way to small peptides that exit the particle. Peptides that are released by the proteasome only exist in the cell for seconds, because they are quickly digested into amino acids by the abundant cytosolic endopeptidases and aminopeptidases. The amino acids can be reutilized to synthesize new proteins or metabolized, yielding energy (48,49).
Although the proteasome principally catalyzes the complete hydrolysis of cell proteins, in a few cases, the 26S proteasome degrades proteins only partially, yielding a biologically active fragment. An example of the latter activity is the generation of a subunit of the transcription factor NF-B (50). For NF-B to be functional in inflammatory processes, the proteasome must digest an inactive precursor molecule and release one half, which functions in transcriptional regulation.
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Proteasome Inhibitors and Cancer Therapy |
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One such synthetic inhibitor, Bortezomib (Velcade, PS-341) has emerged as an important new anticancer drug. Bortezomib has been approved by the US Food and Drug Administration and is widely used for the treatment of multiple myeloma; clinical trials against various other cancers are under active investigation (47,52). The proteasome inhibitors initially were synthesized in an attempt to develop agents that could block the excessive breakdown of muscle proteins in various cachectic states (see section titled Mechanisms That Cause Loss of Muscle Protein in Uremia), but it was discovered that they also could block the activation of NF-B (50), the critical transcription factor that mediates production of many inflammatory cytokines. NF-B also has important antiapoptotic roles that could block the death of cancer cells. However, inhibition of the proteasome was found to induce apoptosis, especially in neoplastic cells and transplanted tumors (40). With the backing of the National Cancer Institute, these agents went into human trials against various cancers, and the special sensitivity of myeloma cells became evident in phase I trials (52).
Surprising, these agent have therapeutic efficacy, even when protein degradation by the proteasome in cancer cells is only partially compromised. Apparently, the myeloma cells are particularly dependent on NF-B for production of essential growth factors (especially IL-6). In addition, malignant plasma cells produce exceptionally large amounts of abnormal Ig that are degraded by the ER-associated degradation–proteasome pathway (see section titled The Proteasome and Immune Surveillance). However, promising responses have been obtained in patients with other hematologic malignancies, and Bortezomib in combination with other chemotherapeutic agents is being tested against other malignancies in clinical trials. Our understanding of the mechanism by which proteasome inhibitors synergize with various cytotoxic agents is incomplete, but combating the antiapoptotic effects of NF-B, especially after there is DNA damage, is an attractive possibility. Surprising, proteasome inhibitors also have benefits in animal models of strokes. The compounds seem to reduce postischemia adhesion of cells and reperfusion injury. Again, the mechanism might involve combating the influence of NF-B. Human trials of the compounds in treatment of strokes soon will be undertaken. Notably, these applications initially were not recognized and probably could not have been predicted. In short, the development of proteasome inhibitors that exhibit several biologic properties emphasizes the enormous benefits that are emerging from basic biochemical research.
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The Proteasome and Immune Surveillance |
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To bind to most MHC class I molecules, peptides have to be eight to nine residues long. Approximately 70 to 80% of proteasome products are too small to serve as antigens (56). The products that are used as antigenic precursors not only are the eight- to nine-residue peptides but also the longer ones with additional amino acids on their amino termini. They are taken up into the ER by a specific peptide transport system, called transporter associated with antigen processing (TAP). Within the ER is a newly discovered aminopeptidase, endoplasmic reticulum aminopeptidase 1 (ERAP1), which has the unusual capacity to trim extra amino acids off the longer precursors and then stops at eight to nine residues, the precise length for binding to MHC molecules (53,57,58).
In inflammatory conditions, the immune cells (e.g., spleen or thymus cells) develop several adaptive mechanism functions that enhance the efficiency of antigen presentation (54). In response to the immune modifier 
-IFN, immune cells express novel types of proteasomes, termed immunoproteasomes, which play a major role in enhancing MHC class I presentation. The immunoproteasomes differ because they contain three novel peptidase subunits in place of the proteases that normally are present. These specialized subunits exhibit different specificities that enable them to cleave proteins differently so that more of the products have the correct features for processing to peptides that are capable of binding to MHC class I molecules (54,59). In addition, -IFN induces a special proteasome-activating complex, PA28. It binds to one end of the 20S proteasome and forms a hybrid 26S particle that has a 19S complex at the other end (60). These hybrid particles degrade ubiquitinated proteins at normal rates but cleave them differently, generating an even higher fraction of peptides that are capable of serving as antigenic precursors. At the same time, -IFN can cause cells to express higher amounts of the TAP transporter, the ERAP1 peptide trimming enzyme, and MHC molecules (54,56,57). Together, these changes stimulate the host defense. Presumably, antigen processing by these systems normally functions well below maximal levels until activation of the host’s defenses is necessary. However, a number of viruses have evolved sophisticated mechanisms to escape immune detection by inhibiting the uptake of proteasome products into the ER by the TAP transporter or by promoting the degradation of MHC class I molecules (55). This competition between immune defenses and viruses demonstrates that the immune systems in higher vertebrates have evolved in terms of modifications of the UPP that otherwise is highly conserved in organisms from yeast to human. These alterations in proteasome structure and the changes in the proteolytic pathway allow efficient antigen presentation and, therefore, the basal recognition of infected or neoplastic cells and their rapid elimination under a variety of conditions.
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Maintenance of Tissue Protein Content in Chronic Kidney Disease |
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Mechanisms That Cause Loss of Muscle Protein in Uremia |
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Because the UPP serves many essential functions in cell regulation and homeostasis, its activation in these states must be highly selective and precisely regulated to avoid the unwanted removal of muscle proteins that are essential for cell function in muscle and other organs. Whereas atrophy seems to affect all muscle cell components, contractile proteins are lost differentially. The specificity of the UPP in protein breakdown is determined by the cell’s content of Ub ligases (E3s), which, as discussed, target specific sets of proteins for degradation. The cellular content of E3s varies among tissues and physiologic states. Two Ub ligases, atrogin-1 (also known as MAFbx) and MuRF-1, are specific constituents of muscle; their expression increases dramatically (eight- to 20-fold) in catabolic states, and they play a critical role in mediating the loss of muscle protein (Figure 5). In mice that lack the genes for atrogin-1 or MuRF-1, muscles grow normally, but if they are denervated, then the rate of muscle atrophy is reduced (74). Muscles of these knockout mice also show reduced atrophy upon fasting. In wild-type animals that are subjected to muscle denervation or disuse, expression of atrogin-1 and MuRF-1 rises quickly just when muscle atrophy is most rapid, and in cultured muscle cells, the content of atrogin-1 mRNA correlates tightly with rates of protein breakdown (75–77). Therefore, the muscle’s content of atrogin-1 mRNA is an excellent biomarker for the rates of proteolysis and rapid wasting.
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As discussed below, the FoxO and NF-B transcription factors act on the promoters for atrogin-1 and MuRF-1 to stimulate their expression, respectively. When activated, FoxO and NF-B cause profound muscle wasting through induction of these E3s together with other atrogenes (75,82,83). Because muscle atrophy that is caused by uremia and other catabolic diseases requires activation of UPP generally and atrogin-1 and MuRF-1 specifically (35,82), efforts are being pursued to reduce the activities of the Ub proteasome pathway or to prevent the induction or activation of these E3s as means of slowing muscle wasting. It is not known how the evidence of inflammation that frequently is present in patients with kidney disease affects muscle protein degradation (64).
Recently, a homologue of E3, E3-II, was identified by Han and colleagues (84). They found a dramatic upregulation of E3-II in atrophying muscles of tumor-bearing rodents. Their results suggest that E3-II or a combination of E3 and E3-II may be responsible for the increased rates of Ub conjugation to muscle proteins by the N-end rule pathway.
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Initial Cleavage of Myofibrillar Proteins in Uremia by Caspase-3 |
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, the N-end rule E3 that recognizes certain amino terminal amino acids (86–88). Because most proteins have N-terminal amino acids that are not recognized by E3, the initial cleavage of myofibrils might explain why activity of the N-end rule pathway in muscle extracts from catabolic animals is increased. Because another protease must breakdown the complex structure of muscle to provide substrates for the UPP, we tested whether caspases may play this critical initial role. Indeed, several catabolic states (sepsis, renal failure) are characterized by high circulating levels of TNF- or insulin resistance, conditions that induce programmed cell death by activating the caspase cascade (89–91). We found that caspase-3 cleaves actomyosin in vitro and in cultured muscle cells to produce and yields substrates that are degraded rapidly by the UPP as well as a 14-kD C-terminal fragment of actin that accumulates in the insoluble fraction of the cell (92). The same processes occur in the muscle of animals with uremia, diabetes, and angiotensin II–induced hypertension, and in humans, a similar 14-kD actin fragment is found in muscle of patients with muscle atrophy as a result of disuse from the pain of osteodystrophy and related to either hemodialysis treatment or burn injury (92–94). Another family of proteases, the calpains, also has been suggested as a mechanism that catalyzes the initial cleavage of myofibrillar proteins in atrophy. Calpains are calcium-dependent cysteine proteases that have been suggested to play roles in several disorders, especially muscular dystrophy. Evidence for calpain’s activation has been reported in muscles of animals with sepsis (95). Although inhibition of the calcium-activated proteases in muscles from rodents with uremia or several other types of atrophy has not been found to block the increase in protein degradation or the degradation of myofibrillar proteins or the accumulation of the 14-kD actin fragment in muscle cells (92), the transgenic expression of calpastatin, an endogenous calpain inhibitor, can reduce denervation atrophy and progression of muscular dystrophy in mice (96). Additional studies are needed to determine whether different catabolic disorders stimulate caspase-3 and/or calpains and their specific roles of these proteases in the breakdown of different muscle proteins.
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Signals That Trigger Muscle Atrophy in Kidney Disease and Other Catabolic States |
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As noted, activation of the UPP in various types of muscle wasting and the coordinated changes in the expression of a set of genes in muscle suggest that these catabolic states activate a common cellular signaling pathway (35). Recent studies have established that in fasting and, presumably, other insulin-deficient states, the fall in protein synthesis and the rise in proteolysis are linked events that occur through decreased signaling by the phosphatidylinositol 3-kinase/Akt (PI3-K/Akt) pathway, which in normal individuals is activated by insulin or IGF-1 (82,103,104). IGF-1 is released by the liver and mediates the anabolic effects of the growth hormone, but it also is an autocrine factor that is released by muscle after exercise. In fasting and disease, when insulin signaling is low, the activity of PI3-K is reduced and there is less production of phosphatidylinositol-3,4,5 phosphate, the active product of PI3-K; the decrease in this regulatory molecule decreases the phosphorylation and activity of the serine/threonine kinase Akt (Figure 5). Activated Akt is a major activator of growth-related processes, and, when overproduced, Akt causes muscle hypertrophy via phosphorylation of the downstream kinases glycogen synthase kinase 3 (GSK3) and mammalian target of rapamycin (mTOR)/S6kinase, which enhance protein synthesis by ribosomes. In many types of atrophy, the reduction in signaling by the PI3-K/Akt pathway leads to reduced mRNA translation and protein production. Rapid atrophy, however, also requires enhanced proteolysis and induction of the E3 atrogin-1 and MuRF-1, leading somehow to enhanced protein degradation in muscle cells (75,76,82). These recent results show that activation of protein degradation and induction of these E3 enzymes in atrophying muscles also result from a decrease in activated Akt (i.e., phosphorylated Akt). One of the targets of activated Akt is the forkhead family of the transcription factors (FoxO1, 3, and 4); when they are not phosphorylated, they migrate into the nucleus and catalyze the transcription of atrogin-1 (75,76,82). Conversely, insulin and IGF-1, by activating PI3-K and Akt, phosphorylate FoxO and suppress expression of atrogin-1 (Figure 5).
In addition to activating atrogin-1/MAFbx, the activation of FoxO will stimulate the cell’s other proteolytic system, the autophagic-lysosomal pathway. This pathway seems to catalyze the degradation of particular cellular components, especially mitochondria. The influence of Akt on the other critical E3 Ub ligase, MuRF-1, is somewhat less clear, but decreased phosphorylation of Akt was found to increase MuRF-1 and atrogin-1 transcription after glucocorticoid treatment or denervation (76). There also is emerging evidence that an unrelated transcription factor, NF-B, can cause overproduction of MuRF-1 and muscle atrophy. Like FoxO3, NF-B, if overproduced, can cause dramatic muscle atrophy and also seems to be required for muscle denervation or disuse atrophy and cancer cachexia (83,105). In the various conditions that are associated with muscle atrophy, both transcription factors seem to contribute to muscle wasting, but their relative importance remains to be resolved.
Besides controlling the expression of E3 Ub ligases, activation of the insulin/IGF-1–-PI3-K/Akt pathway suppresses activation of caspase-3. This would decrease the breakdown of the complex structure of muscle proteins. In insulin-deficient rats that exhibit accelerated muscle protein degradation, we found that the proapoptotic factor Bax is activated, leading to the release of cytochrome C from mitochondria, which in turn activates caspase-3 and increases production of the 14-kD actin fragment (82). Similar changes were seen in cultured muscle cells with genetic or pharmacologic inhibition of PI3-K activity. Together, these recent developments provide evidence that the activation of muscle protein loss in kidney disease and other catabolic conditions occurs through a common signaling pathway that alters transcription of key enzymes that modulate protein synthesis and degradation in complementary ways to cause muscle wasting.
One of the key endocrine factors that are essential for these catabolic responses is glucocorticoids. Administration of high doses of these hormones to rodents, like Cushing’s syndrome in humans, stimulates protein degradation in muscle via atrogin-1, and this response requires FoxO activation (77,106,107). In vivo, glucocorticoids can inhibit insulin/IGF-1 responses, by complex mechanisms. These hormones also exert permissive effects that activate the UPP when other catabolic signals are present. For example, activation of muscle proteolysis does not occur in adrenalectomized animals that are starved or treated with NH4Cl to induce metabolic acidosis or made insulin deficient unless the animals are given a physiologic dose of glucocorticoids (72,108,109). Similarly, the increase in muscle proteolysis that is induced by angiotensin II or sepsis can be blocked by inhibiting the glucocorticoid receptor (93). It is important to note that in these experiments, the same physiologic levels of cortisol did not stimulate muscle protein degradation unless the animals also were acidotic or made insulin deficient; normal animals require higher, pharmacologic doses to cause muscle wasting. These complex regulatory interactions actually make "physiologic sense" because glucocorticoids evolved to integrate stress responses in various tissues. When glucose is needed, an increase in glucocorticoids mobilizes amino acids from muscle protein. At the same time, these hormones induce gluconeogenic enzymes in liver that catalyze conversion of the amino acids to glucose and urea.
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Conclusion |
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Acknowledgments |
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Footnotes |
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References |
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Introduction
Ubiquitin Proteasome Pathway
