A Novel Post-translational Modification of Nucleolin, SUMOylation at Lys-294, Mediates Arsenite-induced Cell Death by Regulating gadd45α mRNA Stability

Zhang, Dongyun; Liang, Yumei; Xie, Qipeng; Gao, Guangxun; Wei, Jinlong; Huang, Haishan; Li, Jingxia; Gao, Jimin; Huang, Chuanshu

doi:10.1074/jbc.m114.598219

Cited by 37 publications

(44 citation statements)

References 77 publications

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“…It has been reported the control of protein expression through mRNA stability in calcium signalling [50]. Zhang et al observed that SUMOylation of Nucleolin at K294 mediated cell death by regulating gadd45 mRNA stability [51]. 3-UTR mRNA pull-down assays and Western blot analysis indicated that the AU binding protein AUF1 interacted with the SERCA2a 3-UTR, which affected mRNA stability [52].…”

Section: Discussionmentioning

confidence: 99%

Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: The myocardial sarcoplasmic reticulum calcium ATPase (SERCA2a) is a pivotal pump responsible for calcium cycling in cardiomyocytes. The present study investigated the effect of luteolin (Lut) on restoring SERCA2a protein level and stability reduced by myocardial ischemia/reperfusion (I/R) injury. We verified a hypothesis that Lut protected against myocardial I/R injury by regulating SERCA2a SUMOylation. Methods: The hemodynamic data, myocardial infarct size of intact hearts, apoptotic analysis, mitochondrial membrane potential (ΔΨm), the level of SERCA2a SUMOylation, and the activity and expression of SERCA2a were examined in vivo and in vitro to clarify the cardioprotective effects of Lut after SUMO1 was knocked down or over-expressed. The putative SUMO conjugation sites in mouse SERCA2a were investigated as the possible regulatory mechanism of Lut. Results: Initially, we found that Lut reversed the SUMOylation and stability of SERCA2a as well as the expression of SUMO1, which were reduced by I/R injury in vitro. Furthermore, Lut increased the expression and activity of SERCA2a partly through SUMO1, thus improving ΔΨm and reducing apoptotic cells in vitro and promoting the recovery of heart function and reducing infarct size in vivo. We also demonstrated that SUMO acceptor sites in mouse SERCA2a involving lysine 585, 480 and 571. Among the three acceptor sites, Lut enhanced SERCA2a stability via lysine 585. Conclusions: Our results suggest that Lut regulates SERCA2a through SUMOylation at lysine 585 to attenuate myocardial I/R injury.

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Section: Discussionmentioning

confidence: 99%

Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice

Liu

et al. 2018

Cell Physiol Biochem

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“…In light of these observations, several hypotheses can be proposed. NCL and NPM1 are both proteins that carry a high number of post-translational modifications, and evidence continues to accumulate suggesting that the nucleoplasmic translocation of both NCL (Kim et al 2005;Zhang et al 2015) and NPM1 (Liu et al 2006;Liu et al 2007;Sato et al 2004;Yogev et al 2008) may be regulated by multiple independent modifications and pathways in response to different genotoxic stresses or in distinct cell types. Moreover, the fact that NPM1 localization to DSBs could only be detected using an antibody recognizing the phosphorylated NPM1-pT199 suggests that any stress-induced relocalization of NPM1, and potentially NCL, may involve a small and specifically-modified population of these highly abundant proteins, and that such fractional relocalization may be unobservable with the currently D r a f t 32 available assays.…”

Section: Nucleoplasmic Translocation: a Mechanism Of Recruitment Or mentioning

confidence: 99%

“…In contrast, NCL binding to and stabilization of a defined G-quadruplex structure within the c-MYC gene promoter contributes to transcriptional repression of this locus, possibly by abolishing binding sites for activating TFs or altering the local chromatin (González et al 2009;González and Hurley 2010). Post-transcriptionally, NCL binding to mRNAs may effect expression of particular proteins, with NCL binding to the p53 mRNA 5'UTR resulting in translational activation, while its binding to gadd45α mRNA in response to arsenite treatment and K294-SUMOylation blocks the degradation of this transcript (Takagi et al 2005;Zhang et al 2015). Remarkably, NCL has even been reported to be constitutively displayed on the cell surface, where it may act as a ligand for particular growth-regulatory ligands and viruses (Fujiki et al 2014;Hovanessian et al 2010;Nisole et al 2002).…”

Section: Ncl Throughout the Cell -Nucleolus Nucleoplasm Cytoplasm Amentioning

confidence: 99%

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Scott

Oeffinger

2016

Biochem. Cell Biol.

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The nucleolus represents a highly multifunctional intranuclear organelle in which, in addition to the canonical ribosome assembly, numerous processes such as transcription, DNA repair and replication, the cell cycle and apoptosis are coordinated. The nucleolus is further a key hub in the sensing of cellular stress and undergoes major structural and compositional changes in response to cellular perturbations.Numerous nucleolar proteins have been identified that, upon nucleolar stress sensing, deploy additional, non-ribosomal roles in the regulation of varied cell processes including cell cycle arrest, arrest of DNA replication, induction of DNA repair, and apoptosis, among others. The highly abundant proteins nucleophosmin (NPM1) and nucleolin (NCL) are two such factors that transit to the nucleoplasm in response to stress, and participate directly in the repair of numerous different DNA damages. This review discusses the contributions made by NCL and/or NPM1 to the different DNA repair pathways employed by mammalian cells to repair DNA insults, and examines the implications of such activities for the regulation, pathogenesis and therapeutic targeting of NPM1 and NCL.

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“…Based on our previous finding that the IL-6 SRE required binding by a complex of cellular proteins including NCL, we mined a published RNAseq dataset for transcripts that were not depleted in SOX expressing 293T cells and were known to be bound by NCL [22,[49][50][51]. A transcript that fit these criteria was growth arrest and DNA damage-inducible 45 beta (GADD45B).…”

Section: Gadd45b Mrna Is Also Resistant To Sox-induced Degradationmentioning

confidence: 99%

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

Muller

Glaunsinger

2017

Preprint

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During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, the viral endonuclease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs, including the transcript encoding interleukin-6 (IL-6), escape SOX-induced cleavage. IL-6 escape is mediated through a 3' UTR RNA regulatory element that overrides the SOX targeting mechanism. Here, we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases. However, it does not impede cleavage by cellular endonucleases. The IL-6 protective sequence may be representative of a larger class of nuclease escape elements, as we identified a similar protective element in the GADD45B mRNA. The IL-6 and GADD45B-derived elements display similarities in their sequence, putative structure, and several associated RNA binding proteins. However, the overall composition of their ribonucleoprotein complexes appears distinct, leading to differences in the breadth of nucleases restricted. These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation.

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A Novel Post-translational Modification of Nucleolin, SUMOylation at Lys-294, Mediates Arsenite-induced Cell Death by Regulating gadd45α mRNA Stability

Cited by 37 publications

References 77 publications

Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice

Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

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