JAZ Requires the Double-stranded RNA-binding Zinc Finger Motifs for Nuclear Localization

Yang, Mingli; May, W. Stratford; Ito, Takahiko

doi:10.1074/jbc.274.39.27399

Cited by 57 publications

(122 citation statements)

References 28 publications

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“…First, differential expression of IgD during B-cell maturation has been shown to occur at the level of mRNA production (12,13,(29)(30)(31) Second, the ZFP318 zinc fingers are of the U1 type defined by the RNA-binding zinc finger in the spliceosomal U1C protein (25,32) and of the zf-C2H2_JAZ superfamily that bind double-stranded RNA or RNA-DNA hybrids (33). Third, both the long and short isoforms of ZFP318 accumulate selectively in the nucleus, with the short isoform localized to subnuclear speckles that contain histone deacetylase 2 (HDAC2) and are adjacent to nuclear speckles containing serine/arginine-rich splicing factor 2 (SRSF2, .…”

Section: Discussionmentioning

confidence: 99%

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Enders¹,

Short²,

Miosge³

et al. 2014

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

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IgD and IgM are produced by alternative splicing of long primary RNA transcripts from the Ig heavy chain (Igh) locus and serve as the receptors for antigen on naïve mature B lymphocytes. IgM is made selectively in immature B cells, whereas IgD is coexpressed with IgM when the cells mature into follicular or marginal zone B cells, but the transacting factors responsible for this regulated change in splicing have remained elusive. Here, we use a genetic screen in mice to identify ZFP318, a nuclear protein with two U1-type zinc fingers found in RNA-binding proteins and no known role in the immune system, as a critical factor for IgD expression. A point mutation in an evolutionarily conserved lysine-rich domain encoded by the alternatively spliced Zfp318 exon 10 abolished IgD expression on marginal zone B cells, decreased IgD on follicular B cells, and increased IgM, but only slightly decreased the percentage of B cells and did not decrease expression of other maturation markers CD21, CD23, or CD62L. A targeted Zfp318 null allele extinguished IgD expression on mature B cells and increased IgM. Zfp318 mRNA is developmentally regulated in parallel with IgD, with little in pro-B cells, moderate amounts in immature B cells, and high levels selectively in mature follicular B cells. These findings identify ZFP318 as a crucial factor regulating the expression of the two major antibody isotypes on the surface of most mature B cells.IgHm | IgHd | immunoglobulin isotype |

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Section: Discussionmentioning

confidence: 99%

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Enders¹,

Short²,

Miosge³

et al. 2014

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

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“…The NLS of the mouse orphan receptor TR2 or Wilms tumor 1 (WT1) can be delimited to one specific zinc finger motif within their multiple zinc fingers (29,30). In contrast, the nuclear localizing activity of EKLF/KLF-1, JAZ, Snail, and Zif268 cannot be ascribed to any particular zinc finger motif (31)(32)(33)(34). In the case of EKLF, for instance, all of the three zinc fingers are necessary for efficient nuclear localization and, notably, each finger shows an incremental effect on the NLS activity (31).…”

Section: Discussionmentioning

confidence: 99%

Nucleocytoplasmic Shuttling of the Zinc Finger Protein EZI Is Mediated by Importin-7-dependent Nuclear Import and CRM1-independent Export Mechanisms

Saijou

Itoh

Kim

et al. 2007

Journal of Biological Chemistry

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Nucleocytoplasmic translocation constitutes a foundation for nuclear proteins to exert their proper functions and hence for various biological reactions to occur normally in eukaryotic cells. We reported previously that EZI/Zfp467, a 12 zinc finger motif-containing protein, localizes predominantly in the nucleus, yet the underlying mechanism still remains elusive. Here we constructed a series of mutant forms of EZI and examined their subcellular localization. The results delineated a noncanonical nuclear localization signal in the region covering the 9th to the 12th zinc fingers, which was necessary for nuclear accumulation of EZI as well as sufficient to confer nuclear localizing ability to a heterologous protein. We also found that the N-terminal domain of EZI is necessary for its nuclear export, the process of which was not sensitive to the CRM1 inhibitor leptomycin B. An interaction proteomics approach and the following co-immunoprecipitation experiments identified the nuclear import receptor importin-7 as a molecule that associated with EZI and, importantly, short interfering RNA-mediated knockdown of importin-7 expression completely abrogated nuclear accumulation of EZI. Taken together, these results identify EZI as a novel cargo protein for importin-7 and demonstrate a nucleocytoplasmic shuttling mechanism that is mediated by importin-7-dependent nuclear localization and CRM1-independent nuclear export.Subcellular distribution of cellular proteins is a foundation for the molecules to exert their proper functions and hence for normal biological reactions to occur. Although some proteins may diffuse freely in the cells, many are destined to localize in a specific subcellular compartment. To achieve proper subcellular localization, such a protein encodes some intrinsic signal, as well as often requires cognate cellular machinery to support its translocation. Thus, identification of such a signal and machinery is a fundamental issue to understand the molecular mechanism whereby a protein exerts its functions.In eukaryotic cells, the nucleus and the cytoplasm are separated by the nuclear membrane. As protein synthesis takes place in the cytoplasm, nuclear proteins must cross the nuclear membrane through the nuclear pore complex (NPC) 4 to enter the nucleus. Likewise, some nuclear proteins are exported from the nucleus to the cytoplasm, in such occasions as recycling of signal transducers, withdrawal of transcription factors, or transport of RNA molecules. Although small particles (less than around 20 -30 kDa) are capable of passing through the NPC freely by passive diffusion, larger molecules require an energy-dependent mechanism mediated by specific nuclear import and export machineries to translocate between the nucleus and cytoplasm (1, 2). It is well established that many, if not all, of these processes depend on the functions of the karyopherin family proteins, which can be largely subdivided into the karyopherin ␣/importin ␣ and karyopherin ␤/importin ␤/exportin subfamilies (hereafter referred to as im...

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“…The zinc fingers of other KLFs, such as those of GKLF (26), UKLF (37), and EKLF (38), have also been shown to act as strong NLS. In some cases, a ''global'' structure of zinc fingers, rather than specific sequences, serves as an NLS (39,40). In others, basic residues within the zinc fingers are critical determinants for nuclear localization (38).…”

Section: Rflat-1/klf13 Recognizes and Binds To The Ctccc Element-rflamentioning

confidence: 99%

Functional Domains and DNA-binding Sequences of RFLAT-1/KLF13, a Krüppel-like Transcription Factor of Activated T Lymphocytes

Song¹,

Patel²,

Thamatrakoln³

et al. 2002

Journal of Biological Chemistry

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RFLAT-1/KLF13, a member of the Krü ppel-like family of transcription factors, was identified as a transcription factor expressed 3-5 days after T lymphocyte activation. It binds to the promoter of the chemokine gene RANTES (regulated on activation normal T cell expressed and secreted) and regulates its ''late'' expression in activated T-cells. In this study, a series of experiments to define the functional domains of RFLAT-1/KLF13 were undertaken to further advance the understanding of the molecular mechanisms underlying transcriptional regulation by this factor. Using the GAL4 fusion system, distinct transcriptional activation and repression domains were identified. The RFLAT-1 minimum activation domain is localized to amino acids 1-35, whereas the repression domain resides in amino acids 67-168. Deletion analysis on the RFLAT-1 protein further supports these domain functions. The RFLAT-1 activation domain is similar to that of its closest family member, basic transcription element-binding protein 1. This domain is highly hydrophobic, and site-directed mutagenesis demonstrated that both negatively charged and hydrophobic residues are important for transactivation. The nuclear localization signal of RFLAT-1 was also identified using the RFLAT-1/green fluorescence protein fusion approach. RFLAT-1 contains two potent, independent nuclear localization signals; one is immediately upstream of the zinc finger DNA-binding domain, and the other is within the zinc fingers. Using mutational analysis, we also determined that the critical binding sequence of RFLAT-1 is CTCCC. The intact CTCCC box on the RANTES promoter is necessary for RFLAT-1-mediated RANTES transcription and is also required for the synergy between RFLAT-1 and NF-B proteins.

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JAZ Requires the Double-stranded RNA-binding Zinc Finger Motifs for Nuclear Localization

Cited by 57 publications

References 28 publications

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Nucleocytoplasmic Shuttling of the Zinc Finger Protein EZI Is Mediated by Importin-7-dependent Nuclear Import and CRM1-independent Export Mechanisms

Functional Domains and DNA-binding Sequences of RFLAT-1/KLF13, a Krüppel-like Transcription Factor of Activated T Lymphocytes

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