ABSTRACT
Ubiquitin modification of many cellular proteins targets them for proteasomal degradation, but in addition can also serve non-proteolytic functions. Over the last years, a significant progress has been made in our understanding of how modification of the substrates of the ubiquitin system is regulated. However, little is known on how the ubiquitin system that is comprised of â¼1500 components is regulated. Here, we discuss how the biggest subfamily within the system, that of the E3 ubiquitin ligases that endow the system with its high specificity towards the numerous substrates, is regulated and in particular via self-regulation mediated by ubiquitin modification. Ligases can be targeted for degradation in a self-catalyzed manner, or through modification mediated by an external ligase(s). In addition, non-proteolytic functions of self-ubiquitination, for example activation of the ligase, of E3s are discussed.
Subject(s)
Ubiquitin-Protein Ligases , Animals , Enzyme Activation , Humans , Hydrolysis , Proteasome Endopeptidase Complex/chemistry , Proteasome Endopeptidase Complex/metabolism , Proto-Oncogene Proteins c-mdm2/chemistry , Proto-Oncogene Proteins c-mdm2/metabolism , Substrate Specificity , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Protein p53/metabolism , Ubiquitin/chemistry , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/chemistry , Ubiquitin-Protein Ligases/physiology , UbiquitinationABSTRACT
The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal in the body are kept under tight control. Central regulators of cellular copper metabolism are the copper-transporting P-type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper-induced trafficking, post-translational modifications and protein-protein interactions. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders.
Subject(s)
Adenosine Triphosphatases/genetics , Cation Transport Proteins/genetics , Hepatolenticular Degeneration/genetics , Menkes Kinky Hair Syndrome/genetics , Adenosine Triphosphatases/chemistry , Adenosine Triphosphatases/physiology , Adenosine Triphosphate/metabolism , Animals , Cation Transport Proteins/chemistry , Cation Transport Proteins/physiology , Copper/metabolism , Copper-Transporting ATPases , Disease Models, Animal , Female , Genotype , Hepatolenticular Degeneration/metabolism , Humans , Male , Menkes Kinky Hair Syndrome/metabolism , Mice , Mice, Mutant Strains , Mutation, Missense , Phenotype , Protein Interaction Mapping , Protein Structure, Tertiary , Rats , Rats, Inbred LEC , Structure-Activity Relationship , ZebrafishABSTRACT
Copper is an essential transition metal but is toxic in excess; therefore, its metabolism needs to be tightly regulated. Defects in the regulation of copper can lead to various disorders characterized by copper deficiency or copper excess. Recently, we characterized the COMMD1 (previously MURR1) gene as the defective gene in canine copper toxicosis. The molecular functions of COMMD1 remain unknown, but significant progress has been made in identifying the cellular processes in which COMMD1 participates, through the identification of proteins interacting with COMMD1. This review discusses how COMMD1 functions as a regulator of not only copper homeostasis but also sodium transport and the NF-kappaB signaling pathway. We outline the possible mechanisms through which COMMD1 exerts these newly identified functions.
Subject(s)
Copper/metabolism , Dog Diseases/genetics , Metal Metabolism, Inborn Errors/veterinary , Proteins/genetics , Adaptor Proteins, Signal Transducing , Animals , Carrier Proteins , Cloning, Molecular , Copper/toxicity , Dogs , Genes, Regulator/physiology , Hepatocytes/cytology , Humans , Metal Metabolism, Inborn Errors/genetics , Models, Animal , NF-kappa B/physiology , Proteins/physiology , Signal Transduction/genetics , Sodium/metabolismABSTRACT
Sarcoidosis of the pancreas is a rare entity. We report on the computed tomographic demonstration of multifocal pancreatic involvement in a patient with systemic sarcoidosis.
Subject(s)
Pancreatic Diseases/diagnostic imaging , Sarcoidosis/diagnostic imaging , Tomography, X-Ray Computed , Aged , Biopsy , Bronchoalveolar Lavage Fluid/cytology , Cholangiography , Cholangiopancreatography, Endoscopic Retrograde , Gallbladder Diseases/diagnostic imaging , Humans , Lung Diseases/pathology , Male , Pancreatic Ducts/diagnostic imaging , Sarcoidosis/pathologyABSTRACT
The history of a man who developed a limited angiitis and granulomatosis of the Wegener type is described. Wegener granulomatosis is a hypersensitivity disease (type III) with an unknown etiology. The typical radiological features, the differential diagnosis and treatment are briefly discussed.
Subject(s)
Granulomatosis with Polyangiitis/diagnostic imaging , Lung/diagnostic imaging , Biopsy , Cyclophosphamide/administration & dosage , Drug Therapy, Combination , Granulomatosis with Polyangiitis/drug therapy , Granulomatosis with Polyangiitis/pathology , Humans , Lung/pathology , Male , Methylprednisolone Hemisuccinate/administration & dosage , Middle Aged , RadiographyABSTRACT
The effects of aqueous extracts of Osbeckia octandra whole plant, Melothria maderaspatana whole plant and Phyllanthus debelis leaves on the human immune system were investigated. The extracts showed strong anticomplement effects on both the classical and alternate pathways of the human complement system in vitro. The effects were dose-dependent and most pronounced in the classical complement pathway assay. The extracts also exhibited a direct dose-dependent inhibition of luminol-induced chemiluminescence of human polymorphonuclear leukocytes upon stimulation with zymosan.
