The splicing factor-associated protein, p32, regulates RNA splicing by inhibiting ASF/SF2 RNA binding and phosphorylation

Petersen-Mahrt, Svend K.; Estmer, Camilla; Öhrmalm, Christina; Matthews, David A.; Russell, W. C.; Akusjärvi, Göran

doi:10.1093/emboj/18.4.1014

Cited by 154 publications

(151 citation statements)

References 53 publications

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“…Another intriguing finding of this study is that FIB also interacts with SF2A-p32, which regulates RNA splicing by inhibiting both the binding of splicing factor ASF/SF2 to pre-mRNA and the phosphorylation of ASF/SF2 (41). Because it may compete with ASF/SF2 for SF2A-p32 binding, mRNA splicing may also be regulated by FIB.…”

Section: Isolation Of Flag-tagged Fib-associated Proteinmentioning

confidence: 76%

Human Fibrillarin Forms a Sub-complex with Splicing Factor 2-associated p32, Protein Arginine Methyltransferases, and Tubulins α3 and β1 That Is Independent of Its Association with Preribosomal Ribonucleoprotein Complexes

Yanagida

Hayano

Yamauchi

et al. 2004

Journal of Biological Chemistry

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Fibrillarin (FIB, Nop1p in yeast) is an RNA methyltransferase found not only in the fibrillar region of the nucleolus but also in Cajal bodies. FIB is essential for efficient processing of preribosomal RNA during ribosome biogenesis, although its precise function in this process and its role in Cajal bodies remain uncertain. Here, we demonstrate that the human FIB N-terminal glycine-and arginine-rich domain (residues 1-77) and its spacer region 1 (78 -132) interact with splicing factor 2-associated p32 (SF2A-p32) and that the FIB methyltransferase-like domain (133-321) interacts with protein-arginine methyltransferase 5 (PRMT5, Janus kinase-binding protein 1). We also show that these proteins associate with several additional proteins, including PRMT1, tubulin ␣3, and tubulin ␤1 to form a sub-complex that is principally independent of the association of FIB with preribosomal ribonucleoprotein complexes that co-immunoprecipitate with the sub-complex in human cells expressing FLAG-tagged FIB. Based on the physical association of FIB with SF2A-p32 and PRMTs, as well as the other reported results, we propose that FIB may coordinate both RNA and protein methylation during the processes of ribosome biogenesis in the nucleolus and RNA editing such as small nuclear (nucleolar) ribonucleoprotein biogenesis in Cajal bodies.Fibrillarin (FIB) 1 is the most abundant protein in the fibrillar regions of the nucleolus where ribosomal RNA transcription and early preribosomal RNA (pre-rRNA) processing take place (1, 2). FIB is also found in Cajal bodies, subnuclear organelles that contain distinct components involved in RNA transcription and editing such as mRNA splicing and small nuclear (nucleolar) ribonucleoprotein (sn(o)RNP) biogenesis (3, 4). FIB is a component of a ribonucleoprotein (RNP) complex that contains U3, U8, and U13 small nucleolar RNAs that exhibit consensus sequence elements denoted box C (5Ј-UGAUGA-3Ј) and box D (5Ј-CUGA-3Ј) (5). The FIB RNP associates with Nop56p, Nop5p/58p, and a 15.5-kDa protein (a counterpart of yeast Snu13p) to form box C/D snoRNP complexes that function in site-specific 2Ј-O-methylation of pre-rRNA (6 -9). FIB is the methyltransferase that catalyzes this 2Ј-O-methylation (10).FIB, or Nop1p in the yeast Saccharomyces cerevisiae, is highly conserved in eukaryotes with respect to sequence, structure, and function (11-17). Deletion of the Nop1 gene in yeast results in inhibition of 2Ј-O-ribose methylation and pre-rRNA processing at sites A 0 to A 2 , indicating that Nop1p is directly involved in both pre-rRNA methylation and processing and ultimately in ribosome assembly (18). Although human FIB is the functional homolog of yeast Nop1p, it only partially complements a yeast nop1-defective mutant (15). Human FIB is a nucleolar autoantigen for the non-hereditary immune disease scleroderma (14). FIB co-localizes with the survival motor neuron (SMN) gene product in both nucleoli and Cajal bodies/gems of primary neurons (19,20). SMN is linked to one of the most common inheritable causes of childho...

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Section: Isolation Of Flag-tagged Fib-associated Proteinmentioning

confidence: 76%

Human Fibrillarin Forms a Sub-complex with Splicing Factor 2-associated p32, Protein Arginine Methyltransferases, and Tubulins α3 and β1 That Is Independent of Its Association with Preribosomal Ribonucleoprotein Complexes

Yanagida

Hayano

Yamauchi

et al. 2004

Journal of Biological Chemistry

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“…Splice alternatives arise from competition between spliceosomes forming at potential splice sites, and control of splice decisions may therefore be achieved by regulation of spliceosome formation. Spliceosome formation is regulated by several mechanisms, including phosphorylation of the SR splicing factor ASF/SF2 (27) and the ratio of spliceosome heterogeneous nuclear ribonucleoprotein A1 to ASF/SF2 proteins (28). A large number of neuron-specific splicing events have been described (2), making it likely that neuronal cells Rϩ ␣ was allowed to autophosphorylate in vitro before tryptic digestion and analysis by mass spectrometry.…”

Section: Discussionmentioning

confidence: 99%

Alternative Splice Variants of Doublecortin-like Kinase Are Differentially Expressed and Have Different Kinase Activities

Burgess

Reiner

2002

Journal of Biological Chemistry

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Alternative splicing of mRNA transcripts expands the range of protein products from a single gene locus. Several splice variants of DCLK (doublecortin-like kinase) have previously been reported. Here, we report the genomic organization underlying the splice variants of DCLK and examine the expression profile of two splice variants affecting the kinase domain of DCLK and CPG16 (candidate plasticity gene 16), one containing an Arg-rich domain and the other affecting the C terminus of the protein. These splice alternatives were differentially expressed in embryonic and adult brain. Both splice variants disrupted DCLK PEST domains; however, all splice variants remained sensitive to proteolysis by calpain. The adult-specific C-terminal splice variant of DCLK had reduced autophosphorylation activity, but similar kinase activity for myelin basic protein relative to the embryonic splice variant. The splice variant adding an Arg-rich domain gained an autophosphorylation site at Ser-382. Although this protein isoform was expressed mainly in the adult brain, the phosphorylated form was strongly enriched in embryonic brain and adult olfactory bulb, suggesting a possible role in migrating neurons.The majority of neuronal cells in the central nervous system are generated during embryogenesis and persist throughout life without further rounds of division and differentiation. Individual neurons accomplish an array of distinct tasks during their life span, including cellular migration, axon extension and pathfinding, synaptogenesis, and participation in mature nervous system function. It has been suggested that to deal with these diverse demands on cellular function, the repertoire of neuronal gene products is enhanced by alternative splicing and RNA editing. Following the description of differential RNA processing of the calcitonin gene (1), alternative splice forms of many gene products have been detected in the central nervous system (2, 3). Doublecortin-like kinase (DCLK) 1 is a serine-threonine kinase expressed in the central nervous system. The N-terminal domain of DCLK is very similar to the doublecortin protein and mediates microtubule localization (4 -6). The C-terminal kinase domain of DCLK resembles members of the family of calcium/calmodulin-dependent protein kinases, but lacks a canonical calmodulin-binding site (7). The human gene was named DCAMKL1 (doublecortin-and Ca 2ϩ /calmodulindependent protein kinase-like protein-1) (8); however, biochemical evidence does not indicate that calcium/calmodulin modulates kinase activity (7).The DCLK locus gives rise to several transcripts through differential splicing and use of alternative promoters (see Fig. 1). The DCL product includes the doublecortin domain, but lacks the kinase domain. DCLK Rϩ is a full-length transcript embracing both doublecortin and kinase domains and includes an additional 16 amino acids enriched in arginine residues (the Arg-rich domain), between the doublecortin and kinase domains (9). Two splice variants affecting the final coding exon of DCLK hav...

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“…It is found in the mitochondria (13)(14)(15), nucleus (14), cytoplasm (16,17) and at the cell surface (18)(19)(20). The N terminus of the immature gC1qR includes a mitochondrial targeting sequence.…”

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confidence: 99%

Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria

Xiao

Liu

et al. 2009

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

124

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The splicing factor-associated protein, p32, regulates RNA splicing by inhibiting ASF/SF2 RNA binding and phosphorylation

Cited by 154 publications

References 53 publications

Human Fibrillarin Forms a Sub-complex with Splicing Factor 2-associated p32, Protein Arginine Methyltransferases, and Tubulins α3 and β1 That Is Independent of Its Association with Preribosomal Ribonucleoprotein Complexes

Human Fibrillarin Forms a Sub-complex with Splicing Factor 2-associated p32, Protein Arginine Methyltransferases, and Tubulins α3 and β1 That Is Independent of Its Association with Preribosomal Ribonucleoprotein Complexes

Alternative Splice Variants of Doublecortin-like Kinase Are Differentially Expressed and Have Different Kinase Activities

Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria

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