TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis

Yin, Haifeng; Guo, Xiaoyun; Chen, Yi; Zeng, Yachang; Mo, Xiaoliang; Hong, Siqi; He, Hui; Li, Jing; Steinmetz, Rachel N.; Liu, Qinghang

doi:10.1172/jci152297

Cited by 22 publications

(19 citation statements)

References 66 publications

(146 reference statements)

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“…It is possible that the deficiency of Tab2 promotes RIPK1 kinase activity and leads to necroptosis in a TAK1-independent manner. Intriguingly, in contrast to the previous finding and ours, a recent work showed that ablation of Tab2 blocks, instead of promotes, TAK1 activation in cardiomyocytes [ 71 ]. It is likely that the discrepancy is caused by different cell types and warrants further investigation.…”

Section: Discussioncontrasting

confidence: 99%

Deficiency of PPP6C protects TNF-induced necroptosis through activation of TAK1

et al. 2022

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Necroptotic cell death is mediated by a super-molecular complex called necrosome which consists of receptor-interacting protein kinase 1 and 3 (RIPK1, RIPK3) and mixed-lineage kinase domain-like protein (MLKL). The role of these kinases has been extensively investigated in the regulation of necroptosis. However, whether the protein phosphatase is involved in necroptosis is still largely unknown. Here, we identified protein phosphatase 6 catalytic subunit (PPP6C) promotes TNF-induced necroptosis by genome-wide CRISPR/Cas9 library screening. We found that PPP6C deficiency protects cells from TNF-induced necroptosis in a phosphatase-activity-dependent manner. Mechanistically, PPP6C acts as a TGF-β activated kinase 1 (TAK1) phosphatase to inactivate its kinase activity. Deletion of PPP6C leads to hyperactivation of TAK1 and reduced RIPK1 kinase activity upon TNF stimulation. We further showed that heterozygous deletion of Ppp6c in mouse gastrointestinal tract alleviates necroptosis-related tissue injury and inflammation. Thus, our study identifies PPP6C as an important regulator of necroptosis and highlights a central role of phosphatase in the regulation of necroptosis-related diseases.

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Section: Discussioncontrasting

confidence: 99%

Deficiency of PPP6C protects TNF-induced necroptosis through activation of TAK1

et al. 2022

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“…We first assessed the distance between supporting SNPs and their predicted target genes. Among the 45 genes at PIP >= 0.8, six (15%) were not the nearest genes to the top GWAS SNPs: ETV1 , TAB2 54 , FGF9 , PLN 55, 56 , CALU 57 and DBX1 . All except DBX1 have previously described impact on cardiovascular physiology or rhythm (Supplementary Table 9).…”

Section: Resultsmentioning

confidence: 99%

Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation

Selewa

Luo

Wasney

et al. 2022

Preprint

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Genome-wide association studies (GWAS) have linked hundreds of loci to cardiac diseases. However, in most loci the causal variants and their target genes remain unknown. We developed a combined experimental and analytical approach that integrates single cell epigenomics with GWAS to prioritize risk variants and genes. We profiled accessible chromatin in single cells obtained from human hearts and leveraged the data to study genetics of Atrial Fibrillation (AF), the most common cardiac arrhythmia. Enrichment analysis of AF risk variants using cell-type-resolved open chromatin regions (OCRs) implicated cardiomyocytes as the main mediator of AF risk. We then performed statistical fine-mapping, leveraging the information in OCRs, and identified putative causal variants in 122 AF-associated loci. Taking advantage of the fine-mapping results, our novel statistical procedure for gene discovery prioritized 45 high-confidence risk genes, highlighting transcription factors and signal transduction pathways important for heart development. We further leveraged our single-cell data to study genetics of gene expression. An unexpected finding from earlier studies is that expression QTLs (eQTLs) are often shared across tissues even though most regulatory elements are cell-type specific. We found that this sharing is largely driven by the limited power of eQTL studies using bulk tissues to detect cell-type-specific regulatory variants. This finding points to an important limitation of using eQTLs to interpret GWAS of complex traits. In summary, our analysis provides a comprehensive map of AF risk variants and genes, and a general framework to integrate single-cell genomics with genetic studies of complex traits.

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“…Numerous previous researches have revealed that apoptosis is associated with dilated cardiomyopathy ( Zhang et al, 2017 ; Mazelin et al, 2016 ; Yin et al, 2022 ). Moreover, Dox increases ROS production in cardiomyocytes, which leads to mitochondrial damage and promotes apoptosis ( Wu et al, 2016 ; Xia et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

I-κB kinase-ε deficiency improves doxorubicin-induced dilated cardiomyopathy by inhibiting the NF-κB pathway

Liu

Yao

et al. 2022

Front. Physiol.

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Dilated cardiomyopathy (DCM) can lead to heart expansion and severe heart failure, but its specific pathogenesis is still elusive. In many cardiovascular diseases, I-κB kinase-ε (IKKε) has been recognized as a pro-inflammatory molecule. In this study, wild-type mice (WT, n = 14) and IKKε knockout mice (IKKε-KO, n = 14) were intraperitoneally injected with a cumulative dose of 25 mg/kg with Dox or Saline five times in 30 days. Finally, the experimental mice were divided into WT + Saline group、WT + DOX group、IKKε-KO + Saline group and IKKε-KO + Dox group. Echocardiography was performed to assess cardiac structure and function. Moreover, the mechanism was validated by immunohistochemistry and western blotting. Our results demonstrated that compared to WT + Dox mice, IKKε-KO + Dox mice exhibited attenuation of dilated cardiomyopathy-related morphological changes and alleviation of heart failure. Additionally, compared to the WT mice after Dox-injected, the expression of fibrosis and proinflammatory were decreased in IKKε-KO mice, and the expression of cardiac gap junction proteins was much higher in IKKε-KO mice. Further testing found that pyroptosis and apoptosis in the myocardium were also ameliorated in IKKε-KO mice compared to WT mice after Dox was injected. Mechanistically, our results showed that deficiency of IKKε might inhibit the phosphorylation of IκBα, p65, RelB, and p100 in mouse heart tissues after Dox stimulation. In summary, our research suggests that IKKε might play an essential role in the development of Dox-induced dilated cardiomyopathy and may be a potential target for the treatment of dilated cardiomyopathy in the future.

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TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis

Cited by 22 publications

References 66 publications

Deficiency of PPP6C protects TNF-induced necroptosis through activation of TAK1

Deficiency of PPP6C protects TNF-induced necroptosis through activation of TAK1

Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation

I-κB kinase-ε deficiency improves doxorubicin-induced dilated cardiomyopathy by inhibiting the NF-κB pathway

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