Identification of a Karyopherin β1/β2 Proline-Tyrosine Nuclear Localization Signal in Huntingtin Protein

Desmond, Carly R.; Atwal, Randy Singh; Xia, Jianrun; Truant, Ray

doi:10.1074/jbc.m112.412379

Cited by 44 publications

(34 citation statements)

References 35 publications

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“…We specifically blocked importin ␤2-mediated nuclear import by expressing a competitive peptide inhibitor of importin ␤2 binding. The M9M peptide incorporates two importin ␤2-binding sites, one from heterogeneous nuclear ribonucleoprotein-A1 and another from heterogeneous nuclear ribonucleoprotein-M that has a high affinity for importin ␤2, thereby allowing it to specifically out-compete cargo from importin ␤2 (27,28). When expressed in cells as an MBP fusion protein, M9M-MBP significantly reduced the level of GFP-anillin localized to the nucleus compared with expressing MBP alone (Fig.…”

Section: Resultsmentioning

confidence: 99%

Importin β2 Mediates the Spatio-temporal Regulation of Anillin through a Noncanonical Nuclear Localization Signal

Chen

Akhshi

Lavoie

et al. 2015

Journal of Biological Chemistry

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Background:Anillin is an evolutionarily conserved protein essential for cytokinesis. Results: Importin ␤2 targets anillin to the nucleus during interphase. Conclusion: Anillin is spatio-temporally regulated during the cell cycle to prevent disruption of the interphase cellular architecture. Significance: Sequestering proteins with key mitotic functions in the nucleus is a vital part of their cell cycle regulation.

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Section: Resultsmentioning

confidence: 99%

Importin β2 Mediates the Spatio-temporal Regulation of Anillin through a Noncanonical Nuclear Localization Signal

Chen

Akhshi

Lavoie

et al. 2015

Journal of Biological Chemistry

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“…Consequently, TIS11 proteins were not included in a list of predicted Transportin cargoes [38]. A recent report on the Transportin-mediated nuclear import of Huntingtin further documents the variability of the PY-NLSs [43]. All together, our and their data suggest that the current definition of PY-NLSs should be revisited to embrace the diversity of all the cargoes imported by this karyopherin.…”

Section: Discussionmentioning

confidence: 91%

A Masked PY-NLS in Drosophila TIS11 and Its Mammalian Homolog Tristetraprolin

et al. 2013

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Many RNA-binding proteins (RBPs) dynamically shuttle between the nucleus and the cytoplasm, often exerting different functions in each compartment. Therefore, the nucleo-cytoplasmic distribution of RBPs has a strong impact on their activity. Here we describe the localization and the shuttling properties of the tandem zinc finger RBP dTIS11, which is the Drosophila homolog of mammalian TIS11 proteins. Drosophila and mammalian TIS11 proteins act as destabilizing factors in ARE-mediated decay. At equilibrium, dTIS11 is concentrated mainly in the cytoplasm. We show that dTIS11 is a nucleo-cytoplasmic shuttling protein whose nuclear export is mediated by the exportin CRM1 through the recognition of a nuclear export signal (NES) located in a different region comparatively to its mammalian homologs. We also identify a cryptic Transportin-dependent PY nuclear localization signal (PY-NLS) in the tandem zinc finger region of dTIS11 and show that it is conserved across the TIS11 protein family. This NLS partially overlaps the second zinc finger ZnF2. Importantly, mutations disrupting the capacity of the ZnF2 to coordinate a Zinc ion unmask dTIS11 and TTP NLS and promote nuclear import. All together, our results indicate that the nuclear export of TIS11 proteins is mediated by CRM1 through diverging NESs, while their nuclear import mechanism may rely on a highly conserved PY-NLS whose activity is negatively regulated by ZnF2 folding.

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“…Recently, we have described the presence of a karyopherin beta2 or transportin-dependent ‘PY-NLS’ in huntingtin between amino acids 172 and 202 (62). This NLS has the ability to mediate nuclear entry by either the importin/karypherin beta1 or the transportin/karyopherin beta2 pathways.…”

Section: Discussionmentioning

confidence: 99%

The huntingtin N17 domain is a multifunctional CRM1 and Ran-dependent nuclear and cilial export signal

Maiuri

Woloshansky

Xia

et al. 2013

Human Molecular Genetics

116

136

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The first 17 amino acids of Huntington’s disease (HD) protein, huntingtin, comprise an amphipathic alpha-helical domain that can target huntingtin to the endoplasmic reticulum (ER). N17 is phosphorylated at two serines, shown to be important for disease development in genetic mouse models, and shown to be modified by agents that reverse the disease phenotype in an HD mouse model. Here, we show that the hydrophobic face of N17 comprises a consensus CRM1/exportin-dependent nuclear export signal, and that this nuclear export activity can be affected by serine phospho-mimetic mutants. We define the precise residues that comprise this nuclear export sequence (NES) as well as the interaction of the NES, but not phospho-mimetic mutants, with the CRM1 nuclear export factor. We show that the nuclear localization of huntingtin depends upon the RanGTP/GDP gradient, and that N17 phosphorylation can also distinguish localization of endogenous huntingtin between the basal body and stalk of the primary cilium. We present a mechanism and multifunctional role for N17 in which phosphorylation of N17 not only releases huntingtin from the ER to allow nuclear entry, but also prevents nuclear export during a transient stress response event to increase the levels of nuclear huntingtin and to regulate huntingtin access to the primary cilium. Thus, N17 is a master localization signal of huntingtin that can mediate huntingtin localization between the cytoplasm, nucleus and primary cilium. This localization can be regulated by signaling, and is misregulated in HD.

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Identification of a Karyopherin β1/β2 Proline-Tyrosine Nuclear Localization Signal in Huntingtin Protein

Cited by 44 publications

References 35 publications

Importin β2 Mediates the Spatio-temporal Regulation of Anillin through a Noncanonical Nuclear Localization Signal

Importin β2 Mediates the Spatio-temporal Regulation of Anillin through a Noncanonical Nuclear Localization Signal

A Masked PY-NLS in Drosophila TIS11 and Its Mammalian Homolog Tristetraprolin

The huntingtin N17 domain is a multifunctional CRM1 and Ran-dependent nuclear and cilial export signal

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