Nuclear targeting signal recognition: a key control point in nuclear transport?

Jans, David A.; Xiao, Cheng; Lam, Mark H. C.

doi:10.1002/(sici)1521-1878(200006)22:6<532::aid-bies6>3.0.co;2-o

Cited by 498 publications

(436 citation statements)

References 86 publications

(258 reference statements)

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“…These data suggest that molecules responsible for nuclear The mechanisms that regulate STAT4 cytoplasmic-nuclear import and nuclear-cytoplasmic export are critical for IFN-␥ production and proliferation of T cells. As was shown for STAT1 nuclear translocation, facilitated transport of STAT1 into the nucleus requires the presence of signal motifs (nuclear localization signals (32)) that are recognized by specific soluble shuttling receptors of the importin/karyopherin family (33)(34)(35)(36)(37). Cytokine-induced transcription is a transient process, lasting only minutes to hours (38).…”

Section: Discussionmentioning

confidence: 99%

Impairment of IL-12-Dependent STAT4 Nuclear Translocation in a Patient with Recurrent Mycobacterium avium Infection

Toyoda

Ido

Hayashi

et al. 2004

The Journal of Immunology

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We examined the immunological abnormality in a patient with recurrent Mycobacterium avium infection. T cells from the patient showed decreased ability both to produce IFN-γ and to proliferate in response to IL-12. Despite decreased expression of IL-12R β1 and β2 chains in the patient’s PHA-activated T cells, there was no difference in IL-12-induced tyrosine and serine phosphorylation of STAT4 in PHA-activated T cells between the patient and healthy subjects, suggesting that IL-12R signals are transmitted to STAT4 in the patient’s PHA-activated T cells. Using EMSA, confocal laser microscopy, and Western blotting, we demonstrated that the nuclear translocation of STAT4 in response to IL-12 is reduced in PHA-activated T cells from the patient when compared with those from healthy subjects. Leptomycin B was used to examine whether nuclear export of STAT4 is increased in the patient’s T cells. However, leptomycin B treatment did not reverse impaired IL-12-induced nuclear accumulation of STAT4. Although the exact mechanism responsible for the impaired STAT4 nuclear translocation in this patient remains unclear, the absence of mutation in the IL-12Rβ1, IL-12Rβ2, STAT4, and STAT4-binding sequence of the IFN-γ gene and preservation of STAT4 tyrosine and serine phosphorylation suggest the existence of a defective STAT4 nuclear translocation. This defect is likely responsible for the impaired STAT4 nuclear translocation in IL-12-stimulated T cells, leading to impairment of both IFN-γ production and cell proliferation. To the best of our knowledge, this is the first report of a patient with atypical mycobacterial infection associated with impairment of STAT4 nuclear translocation.

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Section: Discussionmentioning

confidence: 99%

Impairment of IL-12-Dependent STAT4 Nuclear Translocation in a Patient with Recurrent Mycobacterium avium Infection

Toyoda

Ido

Hayashi

et al. 2004

The Journal of Immunology

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“…Therefore, the presence or absence of a particular import receptor or Nup may determine whether or how efficiently a specific cargo can enter the nucleus. Such a mechanism allows for tissue-and cell-specific expression of different import receptors and Nups that regulate the transport of specific cargoes only when necessary (72). Alterations to this system, or mutation to the import receptors themselves, have obvious potential negative effects on the transport of key cargoes into the nucleus.…”

Section: Alteration To Nuclear Transport Machinerymentioning

confidence: 99%

Nuclear localization signals and human disease

McLane

Corbett

2009

IUBMB Life

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SummaryIn eukaryotic cells, the physical separation of the genetic material in the nucleus from the translation and signaling machinery in the cytoplasm by the nuclear envelope creates a requirement for a mechanism through which macromolecules can enter or exit the nucleus as necessary. Nucleocytoplasmic transport involves the specific recognition of cargo molecules by transport receptors in one compartment followed by the physical relocation of that cargo into the other compartment through regulated pores that perforate the nuclear envelope. The recognition of protein cargoes by their transport receptors occurs via amino acid sequences in cargo proteins called nuclear targeting signals. Both nuclear import and export of proteins are highly regulated processes that control, not only what cargo can enter and/or exit the nucleus, but also when in the cell cycle and in what cell type, the cargo can be transported. Deregulation of the nuclear transport of specific cargoes has been linked to numerous cancers and developmental disorders highlighting the importance of understanding the mechanisms underlying nucleocytoplasmic transport and particularly the modulation of the specific interactions between transporter receptors and nuclear targeting signals within target cargo proteins.2009 IUBMB IUBMB Life, 61(7): [697][698][699][700][701][702][703][704][705][706] 2009

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“…The first step of NLS-dependent nuclear protein import involves NLS recognition by IMPs (23). The amino acid sequence of NLS2 is similar to the basic NLSs, such as that of simian virus SV40 large tumor antigen (T-ag), which is recognized by the IMP ␣/␤ 1 heterodimer.…”

Section: Fig 2 Subcellular Localization Of Endogenous Usp4 In Variomentioning

confidence: 99%

“…Nuclear import is mediated by members of the importin (IMP) superfamily that recognize NLSs. Conversely, nuclear export is mediated by exportins that recognize nuclear export signals (NESs), which are generally leucine-rich elements (23). The best studied exportin is CRM1 (24).…”

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confidence: 99%

Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme

Soboleva

Jans

Johnson-Saliba

et al. 2005

Journal of Biological Chemistry

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The oncogenic deubiquitylating enzyme (DUB) Unp/ Usp4, which binds to the retinoblastoma family of tumor suppressor proteins, was originally described as a nuclear protein. However, more recent studies have shown it to be cytoplasmic. In addition, analysis of its subcellular localization has been complicated by the existence of the paralog Usp15. In this study, we resolved this controversy by investigating the localization of exogenously expressed Usp4 (using red fluorescent proteinUsp4) and of endogenous Usp4 (using highly specific antibodies that can distinguish Usp4 from Usp15). We found that by inhibiting nuclear export with leptomycin B, both exogenous and endogenous Usp4 accumulate in the nucleus. Further, using a Rev-green fluorescent protein-based export assay, we confirmed the existence of a nuclear export signal ( 133 VEVYLLELKL 142 ) in Usp4. In addition, a functional nuclear import signal ( 766 QPQKKKK 772 ) was also identified, which was specifically recognized by importin ␣/␤. Finally, we show that the equilibrium of Usp4 subcellular localization varies between different cell types. Usp4 is thus the first DUB reported to have nucleocytoplasmic shuttling properties. The implications of this shuttling for its function as a DUB are discussed.

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Nuclear targeting signal recognition: a key control point in nuclear transport?

Cited by 498 publications

References 86 publications

Impairment of IL-12-Dependent STAT4 Nuclear Translocation in a Patient with Recurrent Mycobacterium avium Infection

Impairment of IL-12-Dependent STAT4 Nuclear Translocation in a Patient with Recurrent Mycobacterium avium Infection

Nuclear localization signals and human disease

Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme

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