Inhibition of ubiquitin-proteasome pathway–mediated IκBα degradation by a naturally occurring antibacterial peptide

Gao, Youhe; Lecker, Stewart H.; Post, Mark J.; Hietaranta, Antti J.; Li, Jian; Volk, Ruediger; Li, Min; Sato, Kaori; Saluja, Ashok K.; Steer, Michael L.; Goldberg, Alfred L.; Simons, Michael

doi:10.1172/jci9826

Cited by 155 publications

(131 citation statements)

References 54 publications

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“…[Reprinted from Powell et al (176) with permission from Mary Ellen Liebert Publishers. ] peptide is a noncompetitive and reversible allosteric inhibitor that acts by perturbing the conformation of the noncatalytic ␣7-subunit such that cleavage of certain substrates, such as inhibitor B (IB) and hypoxia-inducible factor-1␣ is inhibited, yet overall activity of the proteasome is not affected (72,74). PR39 has been shown to decrease postischemic inflammatory responses in intestine (127) and to improve postischemic cardiac function and decrease infarct size in a rat LAD occlusion model (12) by interfering with NF-B signaling through inhibition of IB degradation.…”

Section: Proteasome Dysfunction In Myocardial Ischemiamentioning

confidence: 99%

The ubiquitin-proteasome system in cardiac physiology and pathology

Powell

2006

American Journal of Physiology-Heart and Circulatory Physiology

146

118

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The ubiquitin-proteasome system (UPS) is the major nonlysosomal pathway for intracellular protein degradation, generally requiring a covalent linkage of one or more chains of polyubiquitins to the protein intended for degradation. It has become clear that the UPS plays major roles in regulating many cellular processes, including the cell cycle, immune responses, apoptosis, cell signaling, and protein turnover under normal and pathological conditions, as well as in protein quality control by removal of damaged, oxidized, and/or misfolded proteins. This review will present an overview of the structure, biochemistry, and physiology of the UPS with emphasis on its role in the heart, if known. In addition, evidence will be presented supporting the role of certain muscle-specific ubiquitin protein ligases, key regulatory components of the UPS, in regulation of sarcomere protein turnover and cardiomyocyte size and how this might play a role in induction of the hypertrophic phenotype. Moreover, this review will present the evidence suggesting that proteasomal dysfunction may play a role in cardiac pathologies such as myocardial ischemia, congestive heart failure, and myofilament-related and idiopathic-dilated cardiomyopathies, as well as cardiomyocyte loss in the aging heart. Finally, certain pitfalls of proteasome studies will be described with the intent of providing investigators with enough information to avoid these problems. This review should provide current investigators in the field with an up-to-date analysis of the literature and at the same time provide an impetus for new investigators to enter this important and rapidly changing area of research.

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Section: Proteasome Dysfunction In Myocardial Ischemiamentioning

confidence: 99%

The ubiquitin-proteasome system in cardiac physiology and pathology

Powell

2006

American Journal of Physiology-Heart and Circulatory Physiology

146

118

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“…A naturally occurring antibacterial peptide, PR39, which reversibly binds the 26S proteasome and blocks the degradation of IB␣ by the ubiquitinpreoteasome pathway, suppresses VCAM-1 and ICAM-1 gene expression in TNF-␣-activated human ECs and reduces the size of myocardial infarction in an in vivo mouse model of coronary ligature. 82 Another possibility to interrupt the NF-B pathway is to block the interaction between NEMO and IKK␤. 83 A cell-permeable NEMO-binding domain (NBD) peptide able to disrupt the IKK␤-NEMO interaction efficiently reduces E-selectin expression in TNF-␣-treated HUVECs.…”

Section: Regulators Of Nf-b Signaling Pathwaymentioning

confidence: 99%

Anti-Inflammatory Mechanisms in the Vascular Wall

Tedgui

Mallat

2001

Circulation Research

384

258

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Abstract-The role of vascular cells during inflammation is critical and is of particular importance in inflammatorydiseases, including atherosclerosis, ischemia/reperfusion, and septic shock. Research in vascular biology has progressed remarkably in the last decade, resulting in a better understanding of the vascular cell responses to inflammatory stimuli. Most of the vascular inflammatory responses are mediated through the IB/nuclear factor-B system. Much recent work shows that vascular inflammation can be limited by anti-inflammatory counteregulatory mechanisms that maintain the integrity and homeostasis of the vascular wall. The anti-inflammatory mechanisms in the vascular wall involve anti-inflammatory external signals and intracellular mediators. The anti-inflammatory external signals include the anti-inflammatory cytokines, transforming growth factor-␤, interleukin-10 and interleukin-1 receptor antagonist, HDL, as well as some angiogenic and growth factors. Physiological laminar shear stress is of particular importance in protecting endothelial cells against inflammatory activation. Its effects are partly mediated through NO production. Finally, endogenous cytoprotective genes or nuclear receptors, such as the peroxisome proliferator-activated receptors, can be expressed by vascular cells in response to proinflammatory stimuli to limit the inflammatory process and the injury. nflammation is a basic pathological mechanism that underlies a variety of diseases. The inflammatory reaction involves the complex interactions between inflammatory cells (neutrophils, lymphocytes, and monocytes/macrophages) and vascular cells (endothelial cells [ECs] and smooth muscle cells [SMCs]). The role of vascular cells during the inflammatory process is critical. Multiple cytokines and growth factors are present at sites of inflammation, and each of these can potentially influence the nature of the inflammatory response. ECs and SMCs must integrate the signals generated by these multiple factors to effectively regulate the immunoinflammatory response through the expression of adhesion molecules, cytokines, chemokines, matrix metalloproteinases, and growth factors. Research in vascular biology has progressed remarkably in the last decade, resulting in a better understanding of the vascular cell responses to inflammatory stimuli and resulting in the identification of major intracellular inflammatory signaling pathways, particularly the IB/nuclear factor-B (NF-B) system. Much recent work shows that vascular inflammation can be limited by anti-inflammatory counteregulatory mechanisms that maintain the integrity and homeostasis of the vascular wall. This might be of particular importance in inflammatory diseases, such as atherosclerosis, septic shock, or ischemia/reperfusion. The purpose of the present review is to describe recent advances in the understanding of the anti-inflammatory mechanisms in vascular cells, focusing on anti-inflammatory external signals and intracellular mediators Original

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“…Using this approach, we could continuously deliver MG-132 to mdx mice over an 8-day period. 19 We administrated different concentrations of MG-132 (delivered at rates of either 1 g, 5 g, or 10 g/kg/24 hours), or the inhibitor-diluent (PBS only), as an important negative control. After 8 days of treatment, the mice were sacrificed.…”

Section: Systemic Treatment With Mg-132mentioning

confidence: 99%

Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

Bonuccelli

Sotgia

Schubert

et al. 2003

The American Journal of Pathology

116

110

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Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is absent in the skeletal muscle of DMD patients and mdx mice. At the plasma membrane of skeletal muscle fibers, dystrophin associates with a multimeric protein complex, termed the dystrophin-glycoprotein complex (DGC). Protein members of this complex are normally absent or greatly reduced in dystrophin-deficient skeletal muscle fibers, and are thought to undergo degradation through an unknown pathway. As such, we reasoned that inhibition of the proteasomal degradation pathway might rescue the expression and subcellular localization of dystrophin-associated proteins. To test this hypothesis, we treated mdx mice with the wellcharacterized proteasomal inhibitor MG-132. First, we locally injected MG-132 into the gastrocnemius muscle, and observed the outcome after 24 hours. Next, we performed systemic treatment using an osmotic pump that allowed us to deliver different concentrations of the proteasomal inhibitor, over an 8-day period. By immunofluorescence and Western blot analysis, we show that administration of the proteasomal inhibitor MG-132 effectively rescues the expression levels and plasma membrane localization of dystrophin, ␤-dystroglycan, ␣-dystroglycan, and ␣-sarcoglycan in skeletal muscle fibers from mdx mice. Furthermore, we show that systemic treatment with the proteasomal inhibitor 1) reduces muscle membrane damage, as revealed by vital staining (with Evans blue dye) of the diaphragm and gastrocnemius muscle isolated from treated mdx mice, and 2) ameliorates the histopathological signs of muscular dystrophy, as judged by hematoxylin and eosin staining of muscle biopsies taken from treated mdx mice. Duchenne muscular dystrophy (DMD) is one of the most prevalent and severe inherited diseases of childhood, characterized by progressive muscular wasting and weakness. The deficient gene product, dystrophin, 1 is a peripheral membrane protein of ϳ426 kd, which is expressed in muscle tissues and the brain. At the plasma membrane, dystrophin associates with a large multimeric complex, termed the dystrophin-glycoprotein complex (DGC). 2 The DGC is composed of two subcomplexes: the dystroglycan complex (␣ and ␤ subunits) and the sarcoglycan complex (␣, ␤, ␥, and ␦ subunits). The Nterminal region of dystrophin interacts directly with the cytoskeletal protein actin, while the dystrophin C-terminal domain binds to the plasma membrane through interactions with ␤-dystroglycan. As such, dystrophin is thought

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Inhibition of ubiquitin-proteasome pathway–mediated IκBα degradation by a naturally occurring antibacterial peptide

Cited by 155 publications

References 54 publications

The ubiquitin-proteasome system in cardiac physiology and pathology

The ubiquitin-proteasome system in cardiac physiology and pathology

Anti-Inflammatory Mechanisms in the Vascular Wall

Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

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