Pediatr Nephrol (2008) 23:527–535 denaturation. For example, in cystic fibrosis, the mutant form of the transmembrane conductance regulator protein (CFTR) is selectively degraded before it reaches the cell surface [23]. The UPS catalyzes destruction of this mutant CFTR because its tertiary structure is abnormal. Another example is the degradation of misfolded proteins within the endoplasmic reticulum. Endoplasmic-reticulum-associated degradation (ERAD) of proteins removes misfolded pro- teins by targeting them for destruction by proteasomes in the cytoplasm [24]. Influencing the function of the immune system The UPS is responsible for creating antigens from the degradation of foreign proteins (e.g. viral particles). The antigens are presented on the major histocompatibility complex as class I molecules. In this way, the 26S proteasome exerts dual roles of removing foreign proteins and creating a stimulus of the immune system [15, 25]. As a source of amino acids When carbohydrate calories are rapidly needed or when cells must respond to catabolic diseases/conditions, there is breakdown of cell proteins, especially skeletal muscle proteins. The UPS degrades muscle proteins to provide amino acids that can be converted to glucose (i.e. gluconeogenesis). An undesired consequence of this activity could be an inappropriate loss of muscle protein. Functions of Ub not associated with proteolysis Ub can also be conjugated to proteins as a monomer (rather than as the typical Ub chain). When this occurs on cell-surface proteins, the protein is internalized into the endocytic pathway to be degraded in lysosomes [26, 27]. Uremia-activated mechanisms that accelerate loss of muscle protein Results from rodent models of CKD have established that accelerated muscle protein catabolism involves many of the same cellular mechanisms that cause muscle wasting in other catabolic conditions, such as cancer, starvation, insulin deficiency/resistance, or sepsis [10, 28]. The principal mechanism causing muscle atrophy in CKD involves activation of the UPS. Evidence for this includes the presence of higher levels of mRNAs encoding certain components of the UPS, as well as a similar pattern of increases and decreases in the expression of about 100 atrophy-related genes (also called atrogenes) [5, 28]. Changes in atrogenes include decreased expression of various growth-related genes and increased expression of components of the UPS. Patients with different clinical 529 conditions associated with muscle atrophy exhibit similar increases in mRNAs encoding components of the UPS (e.g. an increase in mRNAs encoding Ub and proteasome subunits) [11, 29–31]. In these cases, changes in gene expression are most likely due to transcriptional regulation because we have shown that uremia or abnormal insulin responses increase the transcription of Ub and subunits of the proteasome [5, 6, 32]. Additional evidence linking the UPS to protein degradation in catabolism is the finding that the increase in protein degradation in the muscle of rats with CKD (and other muscle-wasting conditions) can be blocked by inhibitors of the proteasome [5, 6, 33]. Considered together, these results indicate that muscle wasting is a specific and carefully orchestrated program. Other questions are why are proteins degraded, and how is the complex program triggered in widely varied pathological conditions (e.g. acidosis in renal failure, low insulin levels in fasting and diabetes, inactivity, or glucocorticoids and cytokines in sepsis and other inflam- matory conditions)? In fasting and in other disease states, acceleration of muscle-protein breakdown mobilizes amino acids, which are used for protein synthesis in tissues and for conversion to glucose in the liver [10]. However, if excessive protein degradation persists, the protein loss will have deleterious effects. In CKD, the breakdown of tissue protein produces nitrogenous waste products, which must be excreted to prevent the accumulation of uremic toxins [3, 10]. Finally, in muscle wasting conditions, contractile proteins are lost differentially, whereas in conditions causing atrophy (e.g. aging), all components of muscle cells seem to be affected. What accounts for muscle-specific response? The answer to this question lies in the involvement of the UPS. The UPS degrades a specific protein depending on which E3 ubiquitin ligase is activated. For example, two Ub ligases, atrogin-1 (also known as MAFbx) and MuRF-1, are found specifically in muscle, and their expression increases dramatically (8- to 20-fold) in catabolic states, causing loss of muscle protein [28, 34, 35]. In mice lacking the genes for either atrogin-1 or MuRF-1, muscles grow normally, but in response to muscle denervation, the ensuing atrophy is 30–50% slower [34]. In addition, the muscle’s content of atrogin-1 mRNA can be considered a biomarker for the rate of proteolysis in muscles responding to a catabolic condition [36–38]. In uremia, the initial cleavage of myofibrillar proteins is mediated by caspase-3 Myofibrillar proteins (including actomyosin) comprise about two thirds of the protein in muscle, the major store of amino acids for new protein synthesis and for gluconeo- genesis. The UPS readily degrades the main proteins in