BAG3 Deficiency Results in Fulminant Myopathy and Early Lethality

Homma, Sachiko; Iwasaki, Masanori; Shelton, G. Diane; Engvall, Eva; Reed, John C.; Takayama, Shinichi

doi:10.2353/ajpath.2006.060250

Cited by 227 publications

(282 citation statements)

References 39 publications

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“…A Pro209Leu mutation in the BAG3 gene was identified in patients with juvenile onset, progressive type, myofibrillar myopathy and DCM 91,98 . Accordingly, Bag3 −/− mice develop cardiomyopathy 99 .…”

Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

140

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

140

126

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“…3 In normal cells, bag3 constitutive expression is limited at very few cell types, including skeletal and heart myocytes. 4 On the other hand, bag3 expression is constitutive in some neoplastic cell types, in which BAG3 protein appears to exert an anti-apoptotic role. From the first evidence of BAG3-mediated survival in B-CLLs, 5 a number of reports confirmed the anti-apoptotic activity of the protein in tumours of different compartments.…”

Section: Introductionmentioning

confidence: 99%

BAG3 controls angiogenesis through regulation of ERK phosphorylation

et al. 2012

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BAG3 is a co-chaperone of the heat shock protein (Hsp) 70, is expressed in many cell types upon cell stress, however, its expression is constitutive in many tumours. We and others have previously shown that in neoplastic cells BAG3 exerts an antiapoptotic function thus favoring tumour progression. As a consequence we have proposed BAG3 as a target of antineoplastic therapies. Here we identify a novel role for BAG3 in regulation of neo-angiogenesis and show that its downregulation results in reduced angiogenesis therefore expanding the role of BAG3 as a therapeutical target. In brief we show that BAG3 is expressed in endothelial cells and is essential for the interaction between ERK and its phosphatase DUSP6, as a consequence its removal results in reduced binding of DUSP6 to ERK and sustained ERK phosphorylation that in turn determines increased levels of p21 and p15 and cell-cycle arrest in the G1 phase.

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“…Remarkably, mice deficient for BAG-3 develop a progressive muscle weakness leading to death shortly after birth (Homma et al, 2006). In addition to aged neuronal cells, muscle cells apparently highly rely on CASA.…”

Section: Casa: Chaperone-assisted Selective Autophagymentioning

confidence: 99%

“…The chaperone machinery then mediates the processing and ubiquitylation of Z-disk components that were damaged during muscle contraction to initiate their disposal through CASA (Arndt et al, 2010). BAG-3 was found to be upregulated in contracting muscles (Arndt et al, 2010), and impairment of BAG-3 activity in transgenic animals and patients resulted in a contraction-dependent disintegration of the Z-disk (Homma et al, 2006;Selcen et al, 2009). The Zdisk component filamin was identified as a critical substrate of CASA in muscle cells (Arndt et al, 2010).…”

Section: Casa: Chaperone-assisted Selective Autophagymentioning

confidence: 99%

“…How the observed pathologies relate to the regulatory role of BAG-3 in chaperone-assisted selective autophagy was recently elucidated (Arndt et al, 2010). In muscle cells, BAG-3 and its chaperone partner HspB8 are specifically localized at the Z-disk, a multiprotein assembly that is required for the bundling and anchoring of actin filaments (Frank et al, 2006;Homma et al, 2006). This localization enables BAG-3 to recruit Hsc/Hsp70 and CHIP to the Z-disk.…”

Section: Casa: Chaperone-assisted Selective Autophagymentioning

confidence: 99%

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Chaperone-assisted degradation: multiple paths to destruction

Kettern

Dreiseidler

Tawo³

et al. 2010

Biological Chemistry

153

155

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Molecular chaperones are well known as facilitators of protein folding and assembly. However, in recent years multiple chaperone-assisted degradation pathways have also emerged, including CAP ( haperone-ssisted roteasomal degradac a p tion), CASA ( haperone-ssisted elective utophagy), and c a s a CMA ( haperone-ediated utophagy). Within these pathc m a ways chaperones facilitate the sorting of non-native proteins to the proteasome and the lysosomal compartment for disposal. Impairment of these pathways contributes to the development of cancer, myopathies, and neurodegenerative diseases. Chaperone-assisted degradation thus represents an essential aspect of cellular proteostasis, and its pharmacological modulation holds the promise to ameliorate some of the most devastating diseases of our time. Here, we discuss recent insights into molecular mechanisms underlying chaperone-assisted degradation in mammalian cells and highlight its biomedical relevance.

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BAG3 Deficiency Results in Fulminant Myopathy and Early Lethality

Cited by 227 publications

References 39 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

BAG3 controls angiogenesis through regulation of ERK phosphorylation

Chaperone-assisted degradation: multiple paths to destruction

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