CRM1-dependent, but not ARE-mediated, nuclear export of<i>IFN-α1</i>mRNA

Kimura, Tetsuya; Hashimoto, Iwao; Nagase, Takahiro; Fujisawa, Jun–ichi

doi:10.1242/jcs.01076

Cited by 63 publications

(47 citation statements)

References 79 publications

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“…For example, the specific CRM1 inhibitor leptomycin B inhibits expression of cyclooxygenase-2 (95) and was shown to cause nuclear retention of c-fos mRNA, whereas general mRNA export appeared not to be affected (66). Furthermore, it was shown that CRM1 mediates the nuclear export of the transcript encoding interferon-␣1 (96). Notably, the truncation of the 3Ј-UTR that contains ARE sequences does not negatively affect the CRM1-dependent nuclear export of the interferon-␣1 mRNA.…”

Section: Discussionmentioning

confidence: 99%

Expression of CD83 Is Regulated by HuR via a Novel cis-Active Coding Region RNA Element

Prechtel

Chemnitz

Schirmer

et al. 2006

Journal of Biological Chemistry

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Dendritic cells (DCs) 3 are the most potent antigen-presenting cells of the immune system and are specialized to sensitize helper and killer T cells during the induction of T cell-mediated immunity (1, 2). In fact, DCs are the only antigen-presenting cells that are able to stimulate naive CD4 ϩ and CD8 ϩ T cells and are therefore referred to as "nature's adjuvant."The CD83 molecule is to date the best known marker for fully mature DCs because CD83 is predominantly expressed on the surface of dendritic lineage cells and cannot be detected on immature DC precursors (3-5). Although its exact function remains to be determined, the fact that CD83 expression is activated during DC maturation, together with co-stimulatory molecules such as CD80 and CD86, suggests a functionally important role for CD83 in DC-mediated T cell immunity (6, 7). This notion is also supported by the fact that inhibition of CD83 expression during DC maturation reduces the T cell stimulatory capacity of these DCs in allo-mixed leukocyte reactions (8). A study using the soluble extracellular domain of CD83 has provided the first direct evidence that this specific surface molecule is indeed functionally important for T cell activation; the soluble CD83 protein completely inhibited DC-mediated T cell stimulation in a concentration-dependent manner in vitro (9). These data were subsequently confirmed in an independent study by using CD83-Ig fusion protein (10). Thus, CD83 appears to play an important functional role in the regulation of DC-mediated T cell-specific immune responses. Therefore, the investigation of the regulation of CD83 expression may provide novel opportunities to modulate DC activity and subsequently DC-mediated immune responses.

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Section: Discussionmentioning

confidence: 99%

Expression of CD83 Is Regulated by HuR via a Novel cis-Active Coding Region RNA Element

Prechtel

Chemnitz

Schirmer

et al. 2006

Journal of Biological Chemistry

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“…We further tested the correlation between mRNA export and antigen presentation by inserting the SL8 epitope in the IFN-α1 mRNA, which is exported through the CRM1 but does not bind the Rev protein (20). In this situation, Rev instead blocks IFN-α1 mRNA export by interfering with the CRM1, resulting in increased SL8 peptide production (Fig.…”

Section: Ribosomal Scanning Of Nonspliced Mrnas Gives Rise To Productmentioning

confidence: 99%

Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway

Apcher

Millot

Daskalogianni

et al. 2013

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

100

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The scanning of maturing mRNAs by ribosomes plays a key role in the mRNA quality control process. When ribosomes first engage with the newly synthesized mRNA, and if peptides are produced, is unclear, however. Here we show that ribosomal scanning of prespliced mRNAs occurs in the nuclear compartment, and that this event produces peptide substrates for the MHC class I pathway. Inserting antigenic peptide sequences in introns that are spliced out before the mRNAs exit the nuclear compartment results in an equal amount of antigenic peptide products as when the peptides are encoded from the main open reading frame (ORF). Taken together with the detection of intron-encoded nascent peptides and RPS6/RPL7-carrying complexes in the perinucleolar compartment, these results show that peptides are produced by a translation event occurring before mRNA splicing. This suggests that ribosomes occupy and scan mRNAs early in the mRNA maturation process, and suggests a physiological role for nuclear mRNA translation, and also helps explain how the immune system tolerates peptides derived from tissue-specific mRNA splice variants.MHC class I restricted antigen presentation | mRNA maturation | nuclear translation R NAs carrying premature termination codons or are recognized as defective in other aspects are prevented from further translation and disposed of by the nonsense-mediated decay (NMD) pathway (1). The detection of premature stop codons is mediated by the scanning ribosome; however, when the ribosomes first engage with the newly synthesized mRNA, and if this event results in the production of peptides, is unclear. Two observations from the field of immunology and the presentation of peptides on MHC class I molecules have highlighted some aspects relevant to the role of the ribosomes in the mRNA maturation process. The first observation is related to the detection of antigenic peptides originating from intron sequences, and the second is related to the observation that the synthesis of antigenic peptide substrates and full-length proteins are two spatiotemporarily distinct events (2-5).The presentation of antigenic peptides on MHC class I molecules allows CD8 + T cells to detect and eliminate cells in which the repertoire of peptide substrates has been altered owing to the presence of viruses or to changes in the presentation of endogenous antigens (6, 7). However, despite the key role of antigen presentation on MHC class I molecules in immune surveillance, the source of peptides for the MHC class I pathway is not yet known. Accumulating evidence indicates that the processing of alternative peptide substrates plays a major role, and that degradation products derived from full-length proteins have limited access to the MHC class I pathway (8-10). We recently demonstrated that pioneer translation products (PTPs) that form antigenic peptide substrates for the MHC class I pathway are produced by a translation event that is distinct from the canonical event giving rise to full-length proteins and does not require the cap-binding ...

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“…Generally, the nuclear export of bulk poly(A) 1 mRNA is mediated in metazoans by the transport receptor NXF1/Tap, together with its small cofactor Nxt1/p15 (reviewed in detail in [30,[53][54][55]). However, it has also been reported that, for example, c-fos mRNA, or the message encoding interferon-a1, is translocated from the nucleus to the cytoplasm by a completely unrelated transport pathway [34,56]. This pathway is characterized by the export receptor : 70 mM) for 3 h. After 1 h, the respective cultures were activated with PMA/ ionomycin as before.…”

mentioning

confidence: 99%

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

et al. 2009

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Fully mature DC and, to a lesser extent, activated T and B cells express CD83, a surface molecule that appears to fulfil an important role in efficient T-cell activation. Recently, it has been shown that CD83 mRNA is transported from the nucleus to the cytoplasm by an uncommon route, involving the cellular RNA-binding protein HuR and the nuclear export receptor CRM1. Moreover, the shuttle phosphoprotein APRIL (ANP32B) has been shown to be required for HuR-mediated nucleocytoplasmic translocation of the CD83 mRNA by acting as an adaptor that links HuR and CRM1. Here, we are able to report that casein kinase 2 (CK2) phosphorylates APRIL on residue threonine244 (Thr 244 ) and demonstrate that the CK2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes CD83 expression in activated Jurkat T cells by interfering with the nucleocytoplasmic translocation of CD83 mRNA. Depletion and knockdown studies demonstrate that the CK2 a 0 subunit is necessary for this regulation, whereas the CK2 a subunit seems to be dispensable. Taken together, the data presented significantly extend our knowledge of the complex regulation of CD83 mRNA processing and provides a novel strategy to interfere with CD83 expression.Key words: APRIL . Casein kinase 2 . CD83 . HuR . Leukocytes IntroductionMature DC are capable of sensitizing even naïve CD4 1 and CD8 1 T cells, and are therefore frequently termed ''nature's adjuvant''. Immature DC reside in the peripheral tissues and upon uptake of antigen and exposure to inflammatory stimuli, they migrate to the peripheral lymph nodes, where now fully matured, they induce antigen-specific T-cell response [1][2][3][4]. The DC maturation process includes the modulation of chemokine and chemokine receptors, as well as the up-regulation of several cytokines, costimulatory and adhesion molecules [5].Human CD83 serves as a major marker molecule for mature DC that belongs to the immunoglobulin super family [6,7]. This membrane-bound protein is also expressed, although to a significant lower extent, on activated T and B cells [7][8][9][10]. Moreover, a soluble form of CD83 is detectable at low levels in sera derived from healthy individuals, whereas in contrast, elevated levels are present in patients suffering from certain hematological malignancies [8,11]. Notwithstanding the fact that accumulating experimental evidence suggests that CD83 plays an important functional role in the regulation of DCmediated T-cell-specific immune response [12][13][14][15][16][17][18][19], the exact function of CD83 remains poorly understood [20][21][22]. Nevertheless, various disease-related findings suggest that CD83 holds great potential for future therapeutic application [23]. For example, EAE can be prevented in mice by applying a soluble form of CD83 [24]. Likewise, in rats, a positive therapeutic effect on experimental autoimmune myasthenia gravis has been reported by application of pentoxifylline, a drug that apparently interferes with CD83 expression [25,26]. Furthermore, CD83 1 DC were found to localize i...

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CRM1-dependent, but not ARE-mediated, nuclear export ofIFN-α1mRNA

Cited by 63 publications

References 79 publications

Expression of CD83 Is Regulated by HuR via a Novel cis-Active Coding Region RNA Element

Expression of CD83 Is Regulated by HuR via a Novel cis-Active Coding Region RNA Element

Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

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