An established scientist has centered his research on protein quality control and degradation in (patho)physiology. Phone: +01 605 658-6345 Address: 414 E Cark Street Vermillion, SD 57069 USA
Objectives: Proteasome functional insufficiency is implicated in a large subset of cardiovascular... more Objectives: Proteasome functional insufficiency is implicated in a large subset of cardiovascular diseases and may play an important role in their pathogenesis, evidenced by increased protein aggregates and ubiquitinated proteins. The regulation of proteasome function is poorly understood, hindering the development of effective strategies to improve proteasome function. We sought to establish the role of protein kinase G (PKG) in these debilitating conditions, for which there is currently no cure. Methods and Results: PKG was manipulated genetically and pharmacologically in cultured cardiomyocytes. Activation of PKG increased proteasome peptidase activities, facilitated proteasome-mediated degradation of surrogate (GFPu) and bona fide misfolded proteins (CryABR120G), and attenuated CryABR120G overexpression-induced accumulation of ubiquitinated proteins and cellular injury. PKG inhibition elicited the opposite responses. Differences in the abundance of the key 26S proteasome subunits Rpt6 and β5 between PKG manipulated and the control groups were not statistically significant, but the isoelectric points of were shifted by PKG activation. In transgenic mice expressing a surrogate substrate (GFPdgn), PKG activation by sildenafil increased myocardial proteasome activities and significantly decreased myocardial GFPdgn protein levels. Sildenafil treatment significantly increased myocardial PKG activity and significantly reduced myocardial accumulation of CryABR120G, ubiquitin conjugates, and aberrant protein aggregates in mice with CryABR120G-based desmin-related cardiomyopathy. No discernible effect on bona fide native substrates of the ubiquitin-proteasome system was observed from PKG manipulation in vitro or in vivo. Conclusions: PKG positively regulates proteasome activities and proteasome-mediated degradation of misfolded proteins likely through posttranslational modifications to proteasome subunits. Improved protein quality control is liekly a new mechanism underlying the benefit of PKG stimulation in treating cardiac diseases. Stimulation of PKG by measures such as sildenafil administration is potentially a novel therapeutic strategy to treat cardiac proteinopathies.
The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded protein... more The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded proteins. Proteasome functional insufficiency (PFI) was observed in experimental proteinopathies and implicated in many human common diseases but its pathogenic role has not been established because a measure to enhance proteasome function in the cell has not been reported until very recently. We have recently discovered that overexpression of proteasome activator 28α (PA28α) enhances proteasome-mediated removal of abnormal proteins in the cell and protects against oxidative stress in cultured cardiomyocytes ( FASEB J 2011; 25(3):883-93 ). Here we have extended the in vitro discoveries to intact animals. First, we created inducible transgenic mice with cardiomyocyte-restricted PA28α overexpression (CR-PA28αOE). CR-PA28αOE does not alter the homeostasis of normal proteins and cardiac function but increases the degradation of a surrogate misfolded protein in the heart. This marks the establishmen...
By indiscriminately degrading portions of cytoplasm for self-supply of nutrients, non-selective a... more By indiscriminately degrading portions of cytoplasm for self-supply of nutrients, non-selective autophagy helps the cell to survive starvation. Selective autophagy, however, removes defective/surplus organelles and protein aggregates, thereby playing an important role in quality control in the cell. A utophagy is involved in the pathophysiology of a variety of disease, including common forms of heart disease. Mechanisms regulating autophagy, especially selective autophagy, remain poorly understood. The COP9 signalosome (CSN) is an evolutionarily conserved protein complex consisting of 8 subunits (CSN1 through CSN8). CSN was purported to regulate ubiquitin-proteasome system (UPS) mediated proteolysis. We recently reported UPS malfunction and the accumulation of ubiquitin positive aggregates in the cardiomyocytes of mice with perinatal cardiomyocyte-restricted Csn8 knockout (CR-Csn8KO), which displayed massive cardiomyocyte necrosis, congestive heart failure, and premature death. Here...
American Journal of Physiology-Heart and Circulatory Physiology, 2006
Recent progresses in signal transduction have revealed that β-catenin signaling controls embryoni... more Recent progresses in signal transduction have revealed that β-catenin signaling controls embryonic development, tumorigenesis, cell shape, and polarity. The role of this pathway in myocyte shape regulation during cardiac hypertrophy and failure is, however, not clearly defined. Since homozygous knockout of β-catenin is embryonically lethal, we have deleted β-catenin genes specifically in the heart of adult mice by crossing loxP-flanked β-catenin mice with transgenic mice expressing tamoxifen-activated MerCreMer protein (MCM) driven by the α-myosin heavy chain promoter. Administration of tamoxifen to homozygous loxP-flanked β-catenin mice positive for MCM induces the deletion of β-catenin only in cardiomyocytes. Immunolabeling with β-catenin antibody demonstrates that 90% of cardiomyocytes completely lose their β-catenin expression but maintain normal rod-shaped morphology. The intercalated disk of cardiomyocytes lacking β-catenin is morphologically unremarkable with normal distribut...
The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular protein degradati... more The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular protein degradation pathways. The UPS mediates the removal of soluble abnormal proteins as well as the targeted degradation of most normal proteins that are no longer needed. Autophagy is generally responsible for bulky removal of defective organelles and for sequestering portions of cytoplasm for lysosomal degradation during starvation. Impaired or inadequate protein degradation in the heart is associated with and may be a major pathogenic factor for a wide variety of cardiac dysfunctions, while enhanced protein degradation is also implicated in the development of cardiac pathology. It was generally assumed that the UPS and autophagy serve distinct functions. Therefore, the functional roles of the UPS and autophagy in the hearts have been largely investigated separately. However, recent advances in understanding the shared mechanisms contributing to UPS alteration and the induction of autophagy have hel...
Alteration of ubiquitin-proteasome system (UPS) mediated protein degradation has been implicated ... more Alteration of ubiquitin-proteasome system (UPS) mediated protein degradation has been implicated in the progression from a large subset of heart disease to congestive heart failure, rendering it extremely important to elucidate the cellular and molecular mechanism by which the UPS is regulated. Cullin-RING ligases (CRLs) represent the largest family of ubiquitin ligases crucial for UPS-dependent proteolysis. Serving as a cullin deneddylase, the COP9 signalosome (CSN) regulates the activity and assembly of CRLs. In the past several years, emerging studies have begun to unveil the role of the CSN and some of the CRLs in cardiomyocytes or the heart under physiological and pathological conditions. This review article will highlight and analyze these recent progresses and provide the author's perspective on the future directions for this research field.
Beyond helping the cell survive from energy starvation via self-eating a portion of cytoplasm, ma... more Beyond helping the cell survive from energy starvation via self-eating a portion of cytoplasm, macroau-tophagy is also capable of targeted removal of defective organelles or cytoplasmic aberrant protein aggregates, thereby playing an important role in quality control in the cell. Impaired or suppressed macroautophagy activity is associated with the progression from a large subset of heart diseases to heart failure and with the development of the vast majority of, if not all, neurodegenerative diseases, the leading causes of death and disability in humans. Hence, a better understanding of the impact of existing and upcoming pharmacotherapies on macroautophagy in the heart and brain will undoubtedly benefit the search for safer and more effective treatment to improve human health. Neddylation is a recently recognized posttranslational modification process that modifies a subset of cellular proteins and is, by virtue of regulating Cullin-RING ligases, essential to ~20% ubiquitin-protea...
Objectives: Proteasome functional insufficiency is implicated in a large subset of cardiovascular... more Objectives: Proteasome functional insufficiency is implicated in a large subset of cardiovascular diseases and may play an important role in their pathogenesis, evidenced by increased protein aggregates and ubiquitinated proteins. The regulation of proteasome function is poorly understood, hindering the development of effective strategies to improve proteasome function. We sought to establish the role of protein kinase G (PKG) in these debilitating conditions, for which there is currently no cure. Methods and Results: PKG was manipulated genetically and pharmacologically in cultured cardiomyocytes. Activation of PKG increased proteasome peptidase activities, facilitated proteasome-mediated degradation of surrogate (GFPu) and bona fide misfolded proteins (CryABR120G), and attenuated CryABR120G overexpression-induced accumulation of ubiquitinated proteins and cellular injury. PKG inhibition elicited the opposite responses. Differences in the abundance of the key 26S proteasome subunits Rpt6 and β5 between PKG manipulated and the control groups were not statistically significant, but the isoelectric points of were shifted by PKG activation. In transgenic mice expressing a surrogate substrate (GFPdgn), PKG activation by sildenafil increased myocardial proteasome activities and significantly decreased myocardial GFPdgn protein levels. Sildenafil treatment significantly increased myocardial PKG activity and significantly reduced myocardial accumulation of CryABR120G, ubiquitin conjugates, and aberrant protein aggregates in mice with CryABR120G-based desmin-related cardiomyopathy. No discernible effect on bona fide native substrates of the ubiquitin-proteasome system was observed from PKG manipulation in vitro or in vivo. Conclusions: PKG positively regulates proteasome activities and proteasome-mediated degradation of misfolded proteins likely through posttranslational modifications to proteasome subunits. Improved protein quality control is liekly a new mechanism underlying the benefit of PKG stimulation in treating cardiac diseases. Stimulation of PKG by measures such as sildenafil administration is potentially a novel therapeutic strategy to treat cardiac proteinopathies.
The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded protein... more The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded proteins. Proteasome functional insufficiency (PFI) was observed in experimental proteinopathies and implicated in many human common diseases but its pathogenic role has not been established because a measure to enhance proteasome function in the cell has not been reported until very recently. We have recently discovered that overexpression of proteasome activator 28α (PA28α) enhances proteasome-mediated removal of abnormal proteins in the cell and protects against oxidative stress in cultured cardiomyocytes ( FASEB J 2011; 25(3):883-93 ). Here we have extended the in vitro discoveries to intact animals. First, we created inducible transgenic mice with cardiomyocyte-restricted PA28α overexpression (CR-PA28αOE). CR-PA28αOE does not alter the homeostasis of normal proteins and cardiac function but increases the degradation of a surrogate misfolded protein in the heart. This marks the establishmen...
By indiscriminately degrading portions of cytoplasm for self-supply of nutrients, non-selective a... more By indiscriminately degrading portions of cytoplasm for self-supply of nutrients, non-selective autophagy helps the cell to survive starvation. Selective autophagy, however, removes defective/surplus organelles and protein aggregates, thereby playing an important role in quality control in the cell. A utophagy is involved in the pathophysiology of a variety of disease, including common forms of heart disease. Mechanisms regulating autophagy, especially selective autophagy, remain poorly understood. The COP9 signalosome (CSN) is an evolutionarily conserved protein complex consisting of 8 subunits (CSN1 through CSN8). CSN was purported to regulate ubiquitin-proteasome system (UPS) mediated proteolysis. We recently reported UPS malfunction and the accumulation of ubiquitin positive aggregates in the cardiomyocytes of mice with perinatal cardiomyocyte-restricted Csn8 knockout (CR-Csn8KO), which displayed massive cardiomyocyte necrosis, congestive heart failure, and premature death. Here...
American Journal of Physiology-Heart and Circulatory Physiology, 2006
Recent progresses in signal transduction have revealed that β-catenin signaling controls embryoni... more Recent progresses in signal transduction have revealed that β-catenin signaling controls embryonic development, tumorigenesis, cell shape, and polarity. The role of this pathway in myocyte shape regulation during cardiac hypertrophy and failure is, however, not clearly defined. Since homozygous knockout of β-catenin is embryonically lethal, we have deleted β-catenin genes specifically in the heart of adult mice by crossing loxP-flanked β-catenin mice with transgenic mice expressing tamoxifen-activated MerCreMer protein (MCM) driven by the α-myosin heavy chain promoter. Administration of tamoxifen to homozygous loxP-flanked β-catenin mice positive for MCM induces the deletion of β-catenin only in cardiomyocytes. Immunolabeling with β-catenin antibody demonstrates that 90% of cardiomyocytes completely lose their β-catenin expression but maintain normal rod-shaped morphology. The intercalated disk of cardiomyocytes lacking β-catenin is morphologically unremarkable with normal distribut...
The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular protein degradati... more The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular protein degradation pathways. The UPS mediates the removal of soluble abnormal proteins as well as the targeted degradation of most normal proteins that are no longer needed. Autophagy is generally responsible for bulky removal of defective organelles and for sequestering portions of cytoplasm for lysosomal degradation during starvation. Impaired or inadequate protein degradation in the heart is associated with and may be a major pathogenic factor for a wide variety of cardiac dysfunctions, while enhanced protein degradation is also implicated in the development of cardiac pathology. It was generally assumed that the UPS and autophagy serve distinct functions. Therefore, the functional roles of the UPS and autophagy in the hearts have been largely investigated separately. However, recent advances in understanding the shared mechanisms contributing to UPS alteration and the induction of autophagy have hel...
Alteration of ubiquitin-proteasome system (UPS) mediated protein degradation has been implicated ... more Alteration of ubiquitin-proteasome system (UPS) mediated protein degradation has been implicated in the progression from a large subset of heart disease to congestive heart failure, rendering it extremely important to elucidate the cellular and molecular mechanism by which the UPS is regulated. Cullin-RING ligases (CRLs) represent the largest family of ubiquitin ligases crucial for UPS-dependent proteolysis. Serving as a cullin deneddylase, the COP9 signalosome (CSN) regulates the activity and assembly of CRLs. In the past several years, emerging studies have begun to unveil the role of the CSN and some of the CRLs in cardiomyocytes or the heart under physiological and pathological conditions. This review article will highlight and analyze these recent progresses and provide the author's perspective on the future directions for this research field.
Beyond helping the cell survive from energy starvation via self-eating a portion of cytoplasm, ma... more Beyond helping the cell survive from energy starvation via self-eating a portion of cytoplasm, macroau-tophagy is also capable of targeted removal of defective organelles or cytoplasmic aberrant protein aggregates, thereby playing an important role in quality control in the cell. Impaired or suppressed macroautophagy activity is associated with the progression from a large subset of heart diseases to heart failure and with the development of the vast majority of, if not all, neurodegenerative diseases, the leading causes of death and disability in humans. Hence, a better understanding of the impact of existing and upcoming pharmacotherapies on macroautophagy in the heart and brain will undoubtedly benefit the search for safer and more effective treatment to improve human health. Neddylation is a recently recognized posttranslational modification process that modifies a subset of cellular proteins and is, by virtue of regulating Cullin-RING ligases, essential to ~20% ubiquitin-protea...
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Papers by Xuejun Wang