PKA rapidly enhances proteasome assembly and activity in in vivo canine hearts

Asai, Mitsutoshi; Tsukamoto, Osamu; Minamino, Tetsuo; Asanuma, Hiroshi; Fujita, Masashi; Asano, Yoshihiro; Takahama, Hiroyuki; Sasaki, Hideyuki; Higo, Shuichiro; Asakura, Masanori; Takashima, Seiji; Hori, Masatsugu; Kitakaze, Masafumi

doi:10.1016/j.yjmcc.2008.11.001

Cited by 91 publications

(99 citation statements)

References 28 publications

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“…Phosphorylation of Rpt6 by PKA is likely to elevate proteasome activity by enhancing proteasome assembly (Fig. 4C) (33). Our findings suggest that rescue of impaired proteasome activity by cAMP-elevating reagents or Rpt6 S120D markedly reduced mHTT aggregates (Fig.…”

Section: Figmentioning

confidence: 57%

“…In particular, we demonstrated herein that low PKA activity in striatal cells expressing mHTT led to low phosphorylation of Rpt6. Because PKA-mediated phosphorylation of Rpt6 enhances the assembly and activity of the proteasome (29,33), suppression of PKA activity further impaired the function of the proteasome (Fig. 5A and B).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the structure of the 26S proteasome may vary greatly among different cell types and various pathophysiological conditions in which proteasome activity is dynamically regulated (5,38). Several earlier studies demonstrated that PKA directly phosphorylates several subunits (including Rpt6) of the UPS and subsequently enhances its activity, at least partially, by promoting proteasome assembly (29,33). Data generated in the present study show that a mutant (Rpt6 S120A ) of Rpt6, a major downstream target of PKA, which cannot undergo phosphorylation by PKA, ablated the beneficial effect of a cAMP-elevating reagent (CGS) on the formation of aggregates (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

Lin

Chang

Chen

et al. 2013

Molecular and Cellular Biology

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Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG repeat in the Huntingtin (HTT) gene. Abnormal regulation of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway occurs during HD progression. Here we found that lower PKA activity was associated with proteasome impairment in the striatum for two HD mouse models (R6/2 and N171-82Q) and in mutant HTT (mHTT)-expressing striatal cells. Because PKA regulatory subunits (PKA-Rs) are proteasome substrates, the mHTT-evoked proteasome impairment caused accumulation of PKA-Rs and subsequently inhibited PKA activity. Conversely, activation of PKA enhanced the phosphorylation of Rpt6 (a component of the proteasome), rescued the impaired proteasome activity, and reduced mHTT aggregates. The dominant-negative Rpt6 mutant (Rpt6 S120A ) blocked the ability of a cAMP-elevating reagent to enhance proteasome activity, whereas the phosphomimetic Rpt6 mutant (Rpt6 S120D ) increased proteasome activity, reduced HTT aggregates, and ameliorated motor impairment. Collectively, our data demonstrated that positive feedback regulation between PKA and the proteasome is critical for HD pathogenesis. Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG repeat in the Huntingtin (HTT) gene. The normal HTT gene has 35 or fewer CAG repeats in its N-terminal region, whereas expansion of the repeat beyond 35 units confers toxicity to the Huntingtin protein (HTT) and evokes HD pathogenesis (1). The major clinical presentations of HD include chorea, cognitive decline, psychiatric symptoms, and a systemic metabolic defect (2). Selective neuronal loss occurs in multiple brain regions, particularly in the striatum and cortex. Since a great number of cellular machineries (including transcription, vesicle transport, molecular chaperones, and the ubiquitin-proteasome system [UPS]) are compromised by the expression of mutant HTT (mHTT) (3), effective removal of mHTT has become one of the most challenging aspects of drug development for HD.The UPS, which degrades misfolded and/or damaged proteins in eukaryotes, is the major regulatory proteolytic pathway. It regulates many essential cellular processes, including transcription, translation, DNA repair, chromatin remodeling, cell survival, signal transduction, protein trafficking, and synaptic plasticity (4). A recent study demonstrated that AAA-ATPase subunits are critical for cell-type-specific regulation of UPS activity (5). Interestingly, UPS activity is under metabolic control. Posttranslational modifications, such as O-GlcNacylation and phosphorylation of 19S subunits, affect the proteolytic activity of the UPS (6). In addition, impaired functioning of the UPS is believed to contribute to the pathogenic processes of many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease (PD), and HD. Recent studies revealed that the UPS might be impaired in HD mouse models and patients (7,8). Intriguingly, although the degradation of polyubiquitin-tagg...

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Section: Figmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

Lin

Chang

Chen

et al. 2013

Molecular and Cellular Biology

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“…20,106 Interestingly, we have demonstrated that ischemic preconditioning and activation of protein kinase A with isoproterenol or forskolin enhance proteasome assembly and activity. 107 Because proteasome inhibition promotes atherosclerosis and cardiac dysfunction, 46,89 protein kinase A activators may attenuate ER-initiated apoptosis signaling through enhanced proteasome function.…”

Section: Pharmacological Agents Targeting Upr Componentmentioning

confidence: 99%

Endoplasmic Reticulum Stress As a Therapeutic Target in Cardiovascular Disease

Minamino

Komuro

Kitakaze

2010

Circulation Research

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432

347

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Cardiovascular disease constitutes a major and increasing health burden in developed countries.Although treatments have progressed, the development of novel treatments for patients with cardiovascular diseases remains a major research goal. The endoplasmic reticulum (ER) is the cellular organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. Stimuli such as oxidative stress, ischemic insult, disturbances in calcium homeostasis, and enhanced expression of normal and/or folding-defective proteins lead to the accumulation of unfolded proteins, a condition referred to as ER stress. ER stress triggers the unfolded protein response (UPR) to maintain ER homeostasis. The UPR involves a group of signal transduction pathways that ameliorate the accumulation of unfolded protein by increasing ER-resident chaperones, inhibiting protein translation and accelerating the degradation of unfolded proteins. The UPR is initially an adaptive response but, if unresolved, can lead to apoptotic cell death. Thus, the ER is now recognized as an important organelle in deciding cell life and death. There is compelling evidence that the adaptive and proapoptotic pathways of UPR play fundamental roles in the development and progression of cardiovascular diseases, including heart failure, ischemic heart diseases, and atherosclerosis. Thus, therapeutic interventions that target molecules of the UPR component and reduce ER stress will be promising strategies to treat cardiovascular diseases. In this review, we summarize the recent progress in understanding UPR signaling in cardiovascular disease and its related therapeutic potential. Future studies may clarify the most promising molecules to be investigated as targets for cardiovascular diseases. (Circ Res. 2010;107:1071-1082.) Key Words: heart failure Ⅲ ischemic heart diseases Ⅲ atherosclerosis Ⅲ ER stress Ⅲ unfolded protein response A lthough the clinical management of heart failure has advanced substantially, 1 and prevention strategies for atherosclerosis focused on managing the established risk factors have progressed markedly, 2 cardiovascular disease still constitutes a major and increasing health burden in developed countries. Thus, the development of novel treatments for patients with cardiovascular diseases remains a major research priority.The endoplasmic reticulum (ER) comprises a complex membranous network found in all eukaryotic cells. It plays a crucial role in the folding of secretory and membrane proteins, calcium homeostasis, and lipid biosynthesis. 3-5 ER Original

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“…There were prior indications that phosphorylation promotes 26S assembly (10,18) and that dephosphorylation of Rpt6 in purified proteasomes promoted their dissociation into 20S and 19S components by disrupting the interaction between Rpt6 and α2 (10). Conversely, phosphorylation by PKA appears to promote 26S in vitro and in vivo (18). The present study provides compelling evidence that phosphorylation promotes 26S assembly in vivo and that this critical step is under physiological regulation.…”

mentioning

confidence: 99%