A redox mechanism underlying nucleolar stress sensing by nucleophosmin

Yang, Kai; Wang, Ming; Zhao, Yuzheng; Sun, Xuxu; Yang, Yi; Xie, Li; Zhou, Aiwu; Chu, Huilin; Zhou, Hu; Xu, Jianrong; Wu, Mian; Yang, Jie; Yi, Jing

doi:10.1038/ncomms13599

Cited by 117 publications

(116 citation statements)

References 86 publications

(142 reference statements)

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“…Cellular stress triggers its dissociation from nucleolar nucleic acids and translocation from the nucleus to the nucleolus, which activates p53 to DNA binding and p53dependent apoptosis. Using live-cell imaging and redox biosensors, Yang et al (91) have demonstrated that NPM1 undergoes glutathionylation on Cys 275 , which triggers its dissociation from nucleolar nucleic acids. In contrast, its mutant protein C275S (cys/ser substitution) could not be glutathionylated and remained bound to DNA under nucleolar stress.…”

Section: P53mentioning

confidence: 99%

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Glutathionylation: a regulatory role of glutathione in physiological processes

Dominko

Đikić

2018

Archives of Industrial Hygiene and Toxicology

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Glutathione (γ-glutamyl-cysteinyl-glycine) is an intracellular thiol molecule and a potent antioxidant that participates in the toxic metabolism phase II biotransformation of xenobiotics. It can bind to a variety of proteins in a process known as glutathionylation. Protein glutathionylation is now recognised as one of important posttranslational regulatory mechanisms in cell and tissue physiology. Direct and indirect regulatory roles in physiological processes include glutathionylation of major transcriptional factors, eicosanoids, cytokines, and nitric oxide (NO). This review looks into these regulatory mechanisms through examples of glutathione regulation in apoptosis, vascularisation, metabolic processes, mitochondrial integrity, immune system, and neural physiology. The focus is on the physiological roles of glutathione beyond biotransformational metabolism.

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Section: P53mentioning

confidence: 99%

“…A recent clinical application of actinomycin D caused substantial remission in patients with acute myeloid leukaemia. This GSH involvement and manipulation with its active binding site on NPM in nucleolar stress sensing may help to develop therapeutic strategies (91).…”

Section: P53mentioning

confidence: 99%

Glutathionylation: a regulatory role of glutathione in physiological processes

Dominko

Đikić

2018

Archives of Industrial Hygiene and Toxicology

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“…Previous data have shown both that NPM1 is a nucleolar/ribosomal stress-induced nucleolar protein and that the interaction between NPM1 and NNV capsid protein may represent a mechanism that is crucial to NNV infection (Mai et al, 2016;Yang et al, 2016). Thus, we hypothesized that RGNNV may induce nucleolar/ribosomal stress via NPM1.…”

Section: Rgnnv Induces Nucleolar/ribosomal Stress In Gs Cellsmentioning

confidence: 96%

RGNNV-induced cell cycle arrest at G1/S phase enhanced viral replication via p53-dependent pathway in GS cells

et al. 2018

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Nervous necrosis virus (NNV) is a ubiquitous pathogen in the aquaculture worldwide. Little is known about the relationship between NNV virus and host cells. Our studies showed that RGNNV infection could induce cell cycle arrest via activation of p53 signaling in cultured host cells. Infection of RGNNV redistributed NPM1, stabilized p53 and inhibited cell proliferation by inducing G1 arrest. RGNNV infection also led to phosphorylation and accumulation of p53 in a time-dependent manner. Furthermore, RGNNV infection upregulated cyclin-dependent kinase inhibitor 1 A (p21) and downregulated cyclin E and cyclin-dependent kinase 2 (CDK2). The expression of genes in the p53 pathway did not change significantly after p53 knockdown by pifithrin-α during RGNNV infection. However, NPM1 knockdown could abrogate RGNNV-induced cell proliferation inhibition, activation of p53 signaling and cell cycle arrest. In addition, RGNNV infection of the cells synchronized in various stages of cell cycle showed that viral genomic RNA and virus titer were higher in the cells released from G1 phase- or S phase-synchronized cells than that in the cells released from the G2 phase-synchronized or asynchronous cells after 18 h p.i. Therefore, our study reveals that RGNNV infection induces the p53-dependent pathway, resulting in a cell cycle arrest at G1 phase in host cells, which might provide a favorable condition for viral replication.

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“…The p53-dependent response relies on the disruption of the interaction between p53 and Mdm2/Hdm2, which results in p53 stabilization and activation. For example, NPM1 undergoes S-glutathionylation upon nucleolar oxidative stress, translocates to the nucleoplasm, and disrupts the p53-Hdm2 interaction [105]. Interestingly, over the last years, several studies have shown that most of the p53-dependent but also p53-independent stress responses are dependent on the activity of free ribosomal proteins (RPs) that have been shown to perform multiple extra-ribosomal functions, including regulation of apoptosis, cell cycle arrest, cell proliferation, and DNA damage repair [106,107].…”

Section: Neddylation In the Nucleolar Stress Responsementioning

confidence: 99%

New Insights into the Mechanisms Underlying NEDD8 Structural and Functional Specificities

Santonico¹

2019

Ubiquitin Proteasome System - Current Insights Into Mechanism Cellular Regulation and Disease

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Ubiquitin (Ub) and ubiquitin-like (Ubl) proteins are small polypeptides that are conjugated to substrates affecting their activity and stability. Cells encode "receptors" containing Ub-/Ubl-binding domains that interpret and translate each modification into appropriate cellular responses. Among the different Ubls, NEDD8, which is the ubiquitin's closest relative, retains many of the structural determinants that enable ubiquitin the ability to target proteins to degradation. Nevertheless, the direct involvement of NEDD8 conjugation to proteasome recruitment has been proved only in a few cases. To date, well-defined major NEDD8 substrates are primarily members of the cullin family, and cullin neddylation does not appear to mark these proteins for degradation. Various studies have demonstrated that selectivity between ubiquitin and NEDD8 is guaranteed by small but substantial differences. Nevertheless, several issues still need to be addressed, mainly concerning which interaction surfaces mediate NEDD8 function and what domains recognize them. Recently, two novel domains identified in KHNYN and N4BP1 proteins have shed new light on this research area. Here, I discuss some recent reports that contributed to shed light on the mechanisms underlining the discrimination between ubiquitin and NEDD8. Understanding the details of these molecular mechanisms represents a prominent facet for the identification of new therapeutic targets.

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A redox mechanism underlying nucleolar stress sensing by nucleophosmin

Cited by 117 publications

References 86 publications

Glutathionylation: a regulatory role of glutathione in physiological processes

Glutathionylation: a regulatory role of glutathione in physiological processes

RGNNV-induced cell cycle arrest at G1/S phase enhanced viral replication via p53-dependent pathway in GS cells

New Insights into the Mechanisms Underlying NEDD8 Structural and Functional Specificities

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