The role of K63‐linked polyubiquitination in cardiac hypertrophy

Ke, Yan; Ponnusamy, Murugavel; Xin, Ying; Wang, Qi; Li, Peifeng; Wang, Kun

doi:10.1111/jcmm.13669

Cited by 17 publications

(4 citation statements)

References 104 publications

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“…9 The K63-linked ubiquitination is crucial in the regulation of pathways such as NF-κB (nuclear factor–κB), which is implicated in the development and progression of cardiac hypertrophy. 30 Researchers have begun to characterize the remaining, “atypical” Ub sites (linked through M1, K6, K11, K27, K29, or K33) by specific E3 Ub ligases. 31,32 For example, K27- and K29-linked ubiquitylation has been associated with lysosomal degradation.…”

Section: Discussionmentioning

confidence: 99%

Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination

Zhao

Zhong

et al. 2021

Circulation

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Background: Without adequate treatment, pathological cardiac hypertrophy induced by sustained pressure overload eventually leads to HF (HF). WW domain- containing E3 ubiquitin protein ligase 1 (WWP1) is an important regulator of aging-related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload-induced cardiac remodeling and HF is yet to be determined. Methods: To examine the correlation of WWP1 with hypertrophy, we analyzed WWP1 expression in patients with HF and mice subjected to transverse aortic constriction (TAC) by Western blotting and immunohistochemical staining. TAC surgery was performed on WWP1 knockout (KO) mice to assess the role of WWP1 in cardiac hypertrophy, heart function was examined by echocardiography and related cellular and molecular markers were examined. Mass spectrometry and coimmunoprecipitation assays were conducted to identify the proteins that interacted with WWP1. Pulse-chase assay, ubiquitination assay, reporter gene assay and an in vivo mouse model via adeno-associated virus serotype 9 (AAV9) were used to explore the mechanisms by which WWP1 regulates cardiac remodeling. AAV9 carrying cTnT promoter driven small hairpin RNA targeting WWP1 (AAV9-cTnT-shWWP1) was administered to investigate its rescue role in TAC-induced cardiac dysfunction. Results: The WWP1 level was significantly increased in the hypertrophic hearts from patients with HF and mice subjected to TAC. The results of echocardiography and histology demonstrated that WWP1 KO protected the heart from TAC-induced hypertrophy. There was a direct interaction between WWP1 and disheveled segment polarity protein 2 (DVL2). DVL2 was stabilized by WWP1 mediated K27-linked polyubiquitination. The role of WWP1 in pressure overload-induced cardiac hypertrophy was mediated by the DVL2/CaMKII/HDAC4/MEF2C signaling pathway. Therapeutic targeting WWP1 almost abolished TAC induced heart dysfunction, suggesting WWP1 as a potential target for treating cardiac hypertrophy and failure. Conclusions: We identified WWP1 as a key therapeutic target for pressure overload induced cardiac remodeling. We also found a novel mechanism regulated by WWP1. WWP1 promotes atypical K27-linked ubiquitin multichain assembly on DVL2 and exacerbates cardiac hypertrophy by the DVL2/CaMKII/HDAC4/MEF2C pathway.

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Section: Discussionmentioning

confidence: 99%

Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination

Zhao

Zhong

et al. 2021

Circulation

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“…It has been reported that Lys63‐linked Ub chains regulate various cellular events, including DNA damage repair (DDR), signal transduction, protein trafficking, and immune response. Misregulation of these pathways leads to stress, accumulation of mutations, cell cycle arrest, and apoptosis that can result in various pathological conditions 33 .…”

Section: Resultsmentioning

confidence: 99%

Selective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair

et al. 2022

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Developing an effective binder for a specific ubiquitin (Ub) chain is a promising approach for modulating various biological processes with potential applications in drug discovery. Here, we combine the Random Non-standard Peptides Integrated Discovery (RaPID) method and chemical protein synthesis to screen an extended library of macrocyclic peptides against synthetic Lys63-linked Di-Ub to discover a specific binder for this Ub chain. Furthermore, next-generation binders are generated by chemical modifications. We show that our potent cyclic peptide is cell-permeable, and inhibits DNA damage repair, leading to apoptotic cell death. Concordantly, a pulldown experiment with the biotinylated analog of our lead cyclic peptide supports our findings. Collectively, we establish a powerful strategy for selective inhibition of protein-protein interactions associated with Lys63-linked Di-Ub using cyclic peptides. This study offers an advancement in modulating central Ub pathways and provides opportunities in drug discovery areas associated with Ub signaling.

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“…Regulation of autophagic mechanisms by K63-linked polyubiquitination has been linked to many pathological processes such as neurodegenerative and cardiovascular diseases, cancer progression, accelerated aging mechanisms and different kinds of infections (Gao et al 2021;Lim and Lim 2011;Liu et al 2018;Yan et al 2018).…”

Section: Medical Outlookmentioning

confidence: 99%

The role of K63-linked polyubiquitin in several types of autophagy

Dósa

Csizmadia

2022

BIOLOGIA FUTURA

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Lysosomal-dependent self-degradative (autophagic) mechanisms are essential for the maintenance of normal homeostasis in all eukaryotic cells. Several types of such self-degradative and recycling pathways have been identified, based on how the cellular self material can incorporate into the lysosomal lumen. Ubiquitination, a well-known and frequently occurred posttranslational modification has essential role in all cell biological processes, thus in autophagy too. The second most common type of polyubiquitin chain is the K63-linked polyubiquitin, which strongly connects to some self-degradative mechanisms in the cells. In this review, we discuss the role of this type of polyubiquitin pattern in numerous autophagic processes.

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The role of K63‐linked polyubiquitination in cardiac hypertrophy

Cited by 17 publications

References 104 publications

Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination

Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination

Selective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair

The role of K63-linked polyubiquitin in several types of autophagy

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