BAG3 plays a central role in proteostasis in the heart

Mizushima, Wataru; Sadoshima, Junichi

doi:10.1172/jci95839

Cited by 22 publications

(15 citation statements)

References 25 publications

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“…3d). The BAG3 molecule has many domains that allows its interaction with several important regulatory proteins and participation in apoptosis and autophagy pathways 26,32,33 . To identify the domain within BAG3 that associates with lamin B, we expressed a series of FLAG-tagged BAG3 mutants (Fig.…”

Section: Resultsmentioning

confidence: 99%

Lamin B is a target for selective nuclear PQC by BAG3: implication for nuclear envelopathies

et al. 2019

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Nuclear envelopathies are recognized genetic disorders affecting individuals with mutations in their genes encoding members of the lamin family of nuclear envelope proteins that are responsible for maintaining the architectural structure of the nucleus. Irregularity in shape and size of the nuclei, nuclear membrane rupture, and appearance of micronuclei in the cytoplasm are among the pathological features of the syndrome. Here, we demonstrate that Bcl2-associated anthanogene-3 (BAG3), a stress-induced co-chaperone protein that by association with heat-shock protein 70 (HSP70) participates in regulation of autophagy, plays a critical role in the integrity of the nuclear membrane in cardiomyocytes. Cells subjected to proteotoxic stress or BAG3 downregulation show perinuclear accumulation of the aberrant ubiquitinated proteins that are often associated with the appearance of misshapen, enlarged, and elongated nuclei. There were dense accumulations of lamin B in the perinuclear area and distribution of lamin B-positive micronuclei in the cytoplasmic space, indicative of nuclear envelope rupture. Overexpression of BAG3 in cells under proteotoxic stress ameliorated pathological nuclear morphology and reduced cytoplasmic distribution of the micronuclei particles. Subcellular co-localization and co-immunoprecipitation demonstrated interaction of lamin B with the BAG domain of BAG3 and HSP70, suggesting the importance of BAG3 in the selective clearance of a surplus of aggregated lamin B that is generated during stress conditions. Our findings define a novel role for BAG3 in nuclear protein quality control and suggest an alternative pathogenetic pathway that contributes to the development of nuclear envelopathies.

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Section: Resultsmentioning

confidence: 99%

Lamin B is a target for selective nuclear PQC by BAG3: implication for nuclear envelopathies

et al. 2019

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“…There are six BAG (Bcl-2-associated athanogene) proteins, evolutionarily conserved throughout different species and named for the presence of at least one 50 amino acid BAG domain [123][124][125]. BAG proteins bind to the ATPase domain of HSP70 family chaperones and serve as a nucleotide exchange factor [126][127][128]. BAG proteins contain additional domains that mediate protein-protein interactions, including single polyproline (PxxP) regions, WW domains, and ubiquitin-like domains.…”

Section: Bag Family Proteinsmentioning

confidence: 99%

With or Without You: Co-chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Altınok¹,

Sanchez‐Hodge²,

Stewart³

et al. 2021

Preprint

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Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintaining protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensuring cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, focusing on cardioprotection, neuroprotection, and cancer. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.

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“…BAG3 is a chaperone protein that is highly expressed in the heart and is associated with the development of human cardiomyopathy (30)(31)(32)(33)(34)(35)(36). The conserved BCL-2-associated anthanogene domain binds to the nucleotide-binding domain of members of the HSP70 family and helps release ADP from the chaperone to facilitate nucleotide cycling (26).…”

Section: Bag3 and Its Interacting Shspsmentioning

confidence: 99%