The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response

Lu, Xinxin; Xu, Haiqi; Xu, Jiaqi; Lu, Saien; You, Shilong; Huang, Xinyue; Zhang, Naijin; Zhang, Lijun

doi:10.3389/fphys.2022.968927

Cited by 10 publications

(9 citation statements)

References 144 publications

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“…NEDD4 family proteins have three functional domains: the N‐terminal C2 domain as a Ca 2+ or phospholipid‐binding motif for membrane binding, the WW domain in the central region that interacts with PPXY motifs or phospho‐serine/threonine residues in substrates, and the HECT domain in the carboxyl terminus that promotes the transfer of ubiquitin to substrates. [ 56 ] We found that NEDD4 could interact with TAK1, and the HECT domain of NEDD4 had the most binding sites for TAK1, which might be the main mechanism by which NEDD4 could reduce TAK1 protein levels by promoting K48‐linked polyubiquitination. K48‐linked polyubiquitination has been reported to negatively regulate the activation of TAK1; for example, FBXW2 degrades TAK1 via targeting TAK1 for K48‐linked polyubiquitination.…”

Section: Discussionmentioning

confidence: 99%

Thrombospondin‐1 Regulates Trophoblast Necroptosis via NEDD4‐Mediated Ubiquitination of TAK1 in Preeclampsia

Hu,

Ma,

Peng

et al. 2024

Advanced Science

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Preeclampsia (PE) is considered as a disease of placental origin. However, the specific mechanism of placental abnormalities remains elusive. This study identified thrombospondin‐1 (THBS1) is downregulated in preeclamptic placentae and negatively correlated with blood pressure. Functional studies show that THBS1 knockdown inhibits proliferation, migration, and invasion and increases the cycle arrest and apoptosis rate of HTR8/SVneo cells. Importantly, THBS1 silencing induces necroptosis in HTR8/SVneo cells, accompanied by the release of damage‐associated molecular patterns (DAMPs). Necroptosis inhibitors necrostatin‐1 and GSK′872 restore the trophoblast survival while pan‐caspase inhibitor Z‐VAD‐FMK has no effect. Mechanistically, the results show that THBS1 interacts with transforming growth factor B‐activated kinase 1 (TAK1), which is a central modulator of necroptosis quiescence and affects its stability. Moreover, THBS1 silencing up‐regulates the expression of neuronal precursor cell‐expressed developmentally down‐regulated 4 (NEDD4), which acts as an E3 ligase of TAK1 and catalyzes K48‐linked ubiquitination of TAK1 in HTR8/SVneo cells. Besides, THBS1 attenuates PE phenotypes and improves the placental necroptosis in vivo. Taken together, the down‐regulation of THBS1 destabilizes TAK1 by activating NEDD4‐mediated, K48‐linked TAK1 ubiquitination and promotes necroptosis and DAMPs release in trophoblast cells, thus participating in the pathogenesis of PE.

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Section: Discussionmentioning

confidence: 99%

Thrombospondin‐1 Regulates Trophoblast Necroptosis via NEDD4‐Mediated Ubiquitination of TAK1 in Preeclampsia

Hu,

Ma,

Peng

et al. 2024

Advanced Science

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“…We found that only MG132 was unable to rescue RNA Pol II from degradation in KSHV-positive BCBL1 cells. Previously, it has been reported that RNA polymerase II ubiquitylation and degradation are important DNA damage responses, conserved from yeast to humans ( 51 ), and identified NEDD4 as the prime E3 ubiquitin ligase that polyubiquitinylates RNA Pol II, leading to its degradation ( 52 ). To determine the role of NEDD4, we knocked down NEDD4 and noticed that RNA Pol II degradation was reversed even in the absence of KSHV during hypoxia.…”

Section: Discussionmentioning

confidence: 99%

KSHV-encoded LANA bypasses transcriptional block through the stabilization of RNA Pol II in hypoxia

Bose,

Singh,

Robertson

2024

mBio

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Hypoxia results from an insufficient supply of oxygen, which results in physiological stress in biological systems. Cells respond to this unfavorable condition by reducing critical cellular functions, which include replication, transcription, and translation. Oncogenic Kaposi sarcoma-associated virus (KSHV) undergoes lytic reactivation in hypoxic conditions. Furthermore, reactivation requires the synthesis of specific viral proteins, both structural and non-structural. Therefore, the virus manipulates the cellular microenvironment to ensure efficient functioning of the cellular transcription machinery, including RNA polymerase II (Pol II), by protecting it from hypoxia-mediated degradation. In this study, we demonstrated that hypoxia induces degradation of RNA Pol II via ubiquitination mediated by the NEDD4 E3 ligase, which results in transcription inhibition. However, in KSHV-infected cells during hypoxia, the virus-encoded latency-associated nuclear antigen interacts with NEDD4, inhibiting its E3 ubiquitin ligase activity and requires complex formation with hypoxia inducible factor HIF1α. This activity inhibits the polyubiquitination of RNA Pol II to maintain steady transcription levels necessary for the synthesis of the essential viral genes needed for successful lytic reactivation. IMPORTANCE Hypoxia can induce the reactivation of Kaposi sarcoma-associated virus (KSHV), which necessitates the synthesis of critical structural proteins. Despite the unfavorable energetic conditions of hypoxia, KSHV utilizes mechanisms to prevent the degradation of essential cellular machinery required for successful reactivation. Our study provides new insights on strategies employed by KSHV-infected cells to maintain steady-state transcription by overcoming hypoxia-mediated metabolic stress to enable successful reactivation. Our discovery that the interaction of latency-associated nuclear antigen with HIF1α and NEDD4 inhibits its polyubiquitination activity, which blocks the degradation of RNA Pol II during hypoxia, is a significant contribution to our understanding of KSHV biology. This newfound knowledge provides new leads in the development of novel therapies for KSHV-associated diseases.

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“…WWP2, encoded by the WWP2 gene, is expressed in several tissues/organs throughout the human body and regulates several cellular, physiological and pathological processes [ 29 , 30 ]. WWP2 was associated with oxidative stress-mediated VSMC injury in different cardiovascular diseases, such as AS, ischemia-reperfusion injury, cardiomyopathy and heart failure [ 31 , 32 ], suggested that WWP2 could be a significant target for treating several cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

Proliferation, migration and phenotypic transformation of VSMC induced via Hcy related to up-expression of WWP2 and p-STAT3

Wang,

Gui,

et al. 2024

PLoS ONE

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To provide a theoretical basis for the prevention and treatment of atherosclerosis (AS), the current study aimed to investigate the mechanism underlying the effect of homocysteine (Hcy) on regulating the proliferation, migration and phenotypic transformation of vascular smooth muscle cells (VSMC) via sirtuin-1 (SIRT1)/signal transducer and activator of transcription 3 (STAT3) through Nedd4-like E3 ubiquitin-protein ligase WWP2 (WWP2). Here, Based on the establishment of ApoE-/- mouse models of high Hcy As and the model of Hcy stimulation of VSMC in vitro to observe the interaction between WWP2 and STAT3 and its effect on the proliferation, migration, and phenotypic transformation of Hcy-induced VSMC, which has not been previously reported. This study revealed that WWP2 could promote the proliferation, migration, and phenotype switch of Hcy-induced VSMC by up-regulating the phosphorylation of SIRT1/STAT3 signaling. Furthermore, Hcy might up-regulate WWP2 expression by inhibiting histone H3K27me3 expression through up-regulated UTX. These data suggest that WWP2 is a novel and important regulator of Hcy-induced VSMC proliferation, migration, and phenotypic transformation.

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The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response

Cited by 10 publications

References 144 publications

Thrombospondin‐1 Regulates Trophoblast Necroptosis via NEDD4‐Mediated Ubiquitination of TAK1 in Preeclampsia

Thrombospondin‐1 Regulates Trophoblast Necroptosis via NEDD4‐Mediated Ubiquitination of TAK1 in Preeclampsia

KSHV-encoded LANA bypasses transcriptional block through the stabilization of RNA Pol II in hypoxia

Proliferation, migration and phenotypic transformation of VSMC induced via Hcy related to up-expression of WWP2 and p-STAT3

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