NoD: a Nucleolar localization sequence detector for eukaryotic and viral proteins

Scott, Michelle S.; Troshin, Peter V; Barton, Geoffrey J.

doi:10.1186/1471-2105-12-317

Cited by 141 publications

(152 citation statements)

References 39 publications

(30 reference statements)

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“…No nucleolar distribution of SERBP1 was suggested by nucleolar proteomic analyzes of the dynamic distribution under virus infection [25,26] or DNA damage [27]. However, two nucleolar localization signals in the N-terminus were determined using NoD [28]. Another putative signal with a value slightly below the 0.8 threshold was present at the C-terminus (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Localization of SERBP1 in stress granules and nucleoli

et al. 2013

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SERPINE1 mRNA-binding protein 1 (SERBP1) is an arginine-methylated RNA-binding protein whose modification affects protein interaction and intracellular localization. In the present study, we show that, under normal growth conditions without stress, SERBP1 interacts with arginine-methylated and stress granule-associated proteins such as heterogeneous nuclear ribonucleoprotein A1, fragile X mental retardation protein and fragile X mental retardation syndrome-related protein 1 in an RNA-dependent manner. We also show that, after arsenite treatment, a proportion of full-length SERBP1 protein co-localizes with the typical stress granule marker T-cell intracellular antigen-1 in the cytoplasmic stress granules. Truncated SERBP1 with an Nterminal, central RG or C-terminal deletion, or single-domain segments comprising the N-terminal, central or C-terminal region, were recruited to stress granules upon arsenite treatment but with reduced efficiency. In addition, upon arsenite treatment, the localization of SERBP1 changed from a diffuse cytoplasmic localization to nuclear-dominant (concentrated in the nucleolus) A similar distribution was observed when cells were treated with the methylation inhibitor adenosine periodate, and was also detected for N-or C-terminal domain deletions and all three single-domain fragments even without stress induction. We further demonstrate that adenosine periodate treatment delays the association/dissociation of SERBP1 with stress granules. Hypomethylation retains SERBP1 in the nucleus/nucleolus regardless of arsenite treatment. Our study indicates that arginine methylation is correlated with recruitment of SERBP to stress granules and nucleoli and its retention therein. To our knowledge, this is the first report of an RNA-binding protein that is shifted simultaneously to cytoplasmic stress granules and nucleoli, two ribonucleoprotein-enriched subcellular compartments, upon stress.

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Section: Discussionmentioning

confidence: 99%

“…Cells in a 35 mm dish grown to~50% confluence were transfected with plasmids using Lipofectamine 2000 (Invitrogen/Life Technologies, Grand Island, NY, [28] as being above the 0.8 threshold are highlighted in yellow. A putative signal slightly below the threshold is highlighted in green.…”

Section: Cell Culture and Treatmentsmentioning

confidence: 99%

Localization of SERBP1 in stress granules and nucleoli

et al. 2013

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“…Prediction of nucleolar localization sequences (NoLS) (26,27) suggested that FGF13 1A contains such elements near its N terminus (Fig. S3C), a region absent in FGF13 isoforms reported to be cytoplasmic (15).…”

Section: Resultsmentioning

confidence: 99%

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

Bublik

Bursać

Sheffer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival ("nononcogene addiction"). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein qualitycontrol capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation.proteostasis | p53 | miR-504 | FGF13 | ribosomal biogenesis

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“…Several previously unknown NoLS have been experimentally confirmed thereafter. 18,27 However, a considerably false positive prediction rate especially among sequences from nuclear proteins raises the question of how NLS and NoLS can be distinguished. The difference in the composition of a standard NLS and the peptides that accumulate in nucleoli is rather subtle, with the NLS being a few basic charged amino acids shorter than, e.g., the nucleolar marker peptide of 10 arginines described by us.…”

Section: -11mentioning

confidence: 99%

Principles of protein targeting to the nucleolus

Martin

Ter-Avetisyan

Herce

et al. 2015

Nucleus

114

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The nucleolus is the hallmark of nuclear compartmentalization and has been shown to exert multiple roles in cellular metabolism besides its main function as the place of rRNA synthesis and assembly of ribosomes. Nucleolar proteins dynamically localize and accumulate in this nuclear compartment relative to the surrounding nucleoplasm. In this study, we have assessed the molecular requirements that are necessary and sufficient for the localization and accumulation of peptides and proteins inside the nucleoli of living cells. The data showed that positively charged peptide entities composed of arginines alone and with an isoelectric point at and above 12.6 are necessary and sufficient for mediating significant nucleolar accumulation. A threshold of 6 arginines is necessary for peptides to accumulate in nucleoli, but already 4 arginines are sufficient when fused within 15 amino acid residues of a nuclear localization signal of a protein. Using a pH sensitive dye, we found that the nucleolar compartment is particularly acidic when compared to the surrounding nucleoplasm and, hence, provides the ideal electrochemical environment to bind poly-arginine containing proteins. In fact, we found that oligo-arginine peptides and GFP fusions bind RNA in vitro. Consistent with RNA being the main binding partner for arginines in the nucleolus, we found that the same principles apply to cells from insects to man, indicating that this mechanism is highly conserved throughout evolution.

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NoD: a Nucleolar localization sequence detector for eukaryotic and viral proteins

Cited by 141 publications

References 39 publications

Localization of SERBP1 in stress granules and nucleoli

Localization of SERBP1 in stress granules and nucleoli

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

Principles of protein targeting to the nucleolus

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