An unexpected role for BAG3 in regulating PARP1 ubiquitination in oxidative stress-related endothelial damage

Zhang, Naijin; Zhang, Ying; Miao, Wei; Shi, Chuning; Chen, Zihan; Wu, Boquan; Zou, Yuanming; Ma, Qifu; You, Shilong; Lu, Saien; Huang, Xinyue; Liu, Jingwei; Xu, Jiaqi; Cao, Liu; Sun, Yingxian

doi:10.1016/j.redox.2022.102238

Cited by 20 publications

(15 citation statements)

References 51 publications

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“…Thus, the role of BAG3 in the inhibition of release of cytochrome c and in the sequestration of the pro-caspases 8 and 9 and its effect on oxidative stress-associated endothelial biology remains controversial [ 42 , 43 ]. It is important to note that there is evidence for BAG3′s role in response to oxidative stress-associated endothelial damage as endothelial specific BAG3 knockout mice demonstrated an increase in oxidative stress-associated endothelial damage and vascular remodeling [ 44 ], whereas BAG3 overexpression significantly decreased the damage associated with this process.…”

Section: Cellular Function Of Bag3mentioning

confidence: 99%

“…One of the most interesting recent observations in the area of BAG3 and the heart was the finding that in addition to BAG3, poly(ADP-ribose) polymerase 1 (PARP1) is also involved in oxidative stress-induced endothelial damage [ 44 ]. Activation of PARP1 promotes the consumption of NAD, signaling a low energy state, and subsequently shuts down high energy consuming processes [ 44 ]. BAG3 is able to bind to the BRCT domain of PARP1 which in turn promotes its degradation.…”

Section: Cellular Function Of Bag3mentioning

confidence: 99%

“…Under normal physiologic conditions, BAG3 is also a substrate of both the acetyltransferase CREB-binding protein (CBP) as well as the deacetylase sirtuin 2 (SIRT2). These two enzymes are responsible for acetylating and deacetylating BAG3 at its K431 residue, respectively [ 44 ]. Importantly, it is the deacetylated form of BAG3 that has been shown to promote the ubiquitination of PARP1 [ 44 ].…”

Section: Cellular Function Of Bag3mentioning

confidence: 99%

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BAG3: Nature’s Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

Brenner

Choudhary

McCormick

et al. 2023

Cells

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BAG3 is a 575 amino acid protein that is found throughout the animal kingdom and homologs have been identified in plants. The protein is expressed ubiquitously but is most prominent in cardiac muscle, skeletal muscle, the brain and in many cancers. We describe BAG3 as a quintessential multi-functional protein. It supports autophagy of both misfolded proteins and damaged organelles, inhibits apoptosis, maintains the homeostasis of the mitochondria, and facilitates excitation contraction coupling through the L-type calcium channel and the beta-adrenergic receptor. High levels of BAG3 are associated with insensitivity to chemotherapy in malignant cells whereas both loss of function and gain of function variants are associated with cardiomyopathy.

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Section: Cellular Function Of Bag3mentioning

confidence: 99%

Section: Cellular Function Of Bag3mentioning

confidence: 99%

Section: Cellular Function Of Bag3mentioning

confidence: 99%

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BAG3: Nature’s Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

Brenner

Choudhary

McCormick

et al. 2023

Cells

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“…Studies have shown that SIRT2 can also deacetylate PARP1 K249, resulting in the ubiquitination and degradation of PARP1 by WW domain-containing protein 2 (WWP2), thereby alleviating the vascular oxidative stress injury caused by PARP1 mediated by angiotensin II (Ang II) [ 107 ]. Alternatively, SIRT2 can deacetylate K431 of Bcl-2-associated athanogene 3 (BAG3), thereby mediating BAG3 binding to PARP1 to promote the ubiquitination degradation of WWP2 at PARP1 K249 to protect against oxidative damage [ 108 ].…”

Section: Sirt2 and Metabolic Disordersmentioning

confidence: 99%

“…Studies have shown that during atherosclerosis, SIRT2 can inhibit the occurrence and development of atherosclerotic macrophages by inhibiting the polarization of macrophages [ 139 ]. Alternatively, SIRT2 can directly act on its target Nrf2/FOXO3/PARP1 and indirectly act on PARP1 by deacetylating BAG3, which alleviates the further aggravation of hypertension and oxidative stress, prevents intraluminal occlusion and stenosis from causing organic lesions, and avoids the occurrence of coronary heart disease (CHD) of myocardial ischaemia [ 97 , 98 , 107 , 108 ]. Furthermore, in acute myocardial infarction (AMI), functional DNA sequence variants (DSVs) can alter the SIRT2 levels by affecting the transcriptional activity of the SIRT2 promoter, leading to the progression of AMI into severe disease [ 140 ].…”

Section: Role Of Sirt2 In Diseasementioning

confidence: 99%

Multiple Roles of SIRT2 in Regulating Physiological and Pathological Signal Transduction

et al. 2022

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Sirtuin 2 (SIRT2), as a member of the sirtuin family, has representative features of evolutionarily highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity. In addition, SIRT2, as the only sirtuin protein colocalized with tubulin in the cytoplasm, has its own functions and characteristics. In recent years, studies have increasingly shown that SIRT2 can participate in the regulation of gene expression and regulate signal transduction in the metabolic pathway mainly through its post-translational modification of target genes; thus, SIRT2 has become a key centre in the metabolic pathway and participates in the pathological process of metabolic disorder-related diseases. In this paper, it is discussed that SIRT2 can regulate all aspects of gene expression, including epigenetic modification, replication, transcription and translation, and post-translational modification, which enables SIRT2 to participate in energy metabolism in life activities, and it is clarified that SIRT2 is involved in metabolic process-specific signal transduction mechanisms. Therefore, SIRT2 can be involved in metabolic disorder-related inflammation and oxidative stress, thereby triggering the occurrence of metabolic disorder-related diseases, such as neurodegenerative diseases, tumours, diabetes, and cardiovascular diseases. Currently, although the role of SIRT2 in some diseases is still controversial, given the multiple roles of SIRT2 in regulating physiological and pathological signal transduction, SIRT2 has become a key target for disease treatment. It is believed that with increasing research, the clinical application of SIRT2 will be promoted.

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Stanniocalcin‐1 Promotes PARP1‐Dependent Cell Death via JNK Activation in Colitis

Zhu,

Xie,

Yang

et al. 2023

Advanced Science

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Stanniocalcin‐1 (STC1) is upregulated by inflammation and modulates oxidative stress‐induced cell death. Herein, the function of STC1 in colitis and stress‐induced parthanatos, a newly identified type of programmed necrotic cell death dependent on the activation of poly‐ADP ribose polymerase‐1 (PARP1) is investigated. Results show that STC1 expression is markedly increased in the inflamed colonic mucosa of Crohn's disease (CD) patients and chemically‐induced mice colitis models. Evaluation of parthanatos severity and pro‐inflammatory cytokine expression shows that intestinal‐specific Stc1 knockout (Stc1INT‐KO) mice are resistant to dextran sulfate sodium (DSS)‐induced colitis and exhibit lower disease severity. STC1‐overexpressing cells show an increased degree of parthanatos and proinflammatory cytokine expression, whereas STC1‐knockout cells show a decreased degree of parthanatos. Co‐immunoprecipitation, mass spectrometry, and proteomic analyses indicate that STC1 interacts with PARP1, which activates the JNK pathway via PARP1–JNK interactions. Moreover, inhibition of PARP1 and JNK alleviates parthanatos and inflammatory injuries triggered by STC1 overexpression. Finally, following restoration of Stc1 and Parp1 expression by adeno‐associated viruses, and overexpression of Stc1 and Parp1 aggravated DSS‐induced colitis in Stc1INT‐KO mice. In conclusion, STC1 mediates oxidative stress‐associated parthanatos and aggravates inflammation via the STC1–PARP1–JNK interactions and subsequent JNK pathway activation in CD pathogenesis.

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An unexpected role for BAG3 in regulating PARP1 ubiquitination in oxidative stress-related endothelial damage

Cited by 20 publications

References 51 publications

BAG3: Nature’s Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

BAG3: Nature’s Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

Multiple Roles of SIRT2 in Regulating Physiological and Pathological Signal Transduction

Stanniocalcin‐1 Promotes PARP1‐Dependent Cell Death via JNK Activation in Colitis

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