The Fission Yeast ES2 Homologue, Bis1, Interacts with the Ish1 Stress-responsive Nuclear Envelope Protein

Taricani, Lorena; Tejada, Max L.; Young, Paul G.

doi:10.1074/jbc.m110686200

Cited by 31 publications

(39 citation statements)

References 49 publications

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“…GFPtagged ESS-2 was primarily localized to the nucleus, with occasional detection of one or a few bright nuclear puncta ( Figure 5F). Similar nuclear puncta have also been reported for the fission yeast homolog, Bis1 (Taricani et al 2002). Expression of cDNA isolated from ess-2(ok3569) did not rescue ess-2(tm4246).…”

supporting

confidence: 52%

“…The fission yeast ortholog of ES2, Bis1, was found as an interacting protein to a stress-response nuclear envelope protein Ish1 (induced in stationary phase 1) and plays a role in viability in the stationary phase (Taricani et al 2002). Human ES2/DGCR14 is highly expressed in heart, brain, and skeletal muscle and is located in the common chromosome region on 22q11.2 deleted in patients with DiGeorge syndrome and velocardiofacial syndrome Rizzu et al 1996;Gong et al 1997).…”

Section: Ess-2 Regulates Mrna Splicingmentioning

confidence: 99%

“…This protein family is conserved from fission yeast Schizosaccharomyces pombe to human and contains two conserved coiled-coil regions in its N-terminal based on the MARCOIL program (Delorenzi and Speed 2002) ( Figure 5B and Figure S6). Both yeast homolog Bis1 and mouse ES2 are localized in the nucleus (Lindsay et al 1998;Taricani et al 2002). A recent large-scale protein interactome study identified human ES2/DGCR14 as a noncore component of the spliceosome C complex (Hegele et al 2012), suggesting that the ESS-2 protein family might function in mRNA splicing.…”

mentioning

confidence: 99%

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Systematic Analyses of rpm-1 Suppressors Reveal Roles for ESS-2 in mRNA Splicing in Caenorhabditis elegans

2014

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The PHR (Pam/Highwire/RPM-1) family of ubiquitin E3 ligases plays conserved roles in axon patterning and synaptic development. Genetic modifier analysis has greatly aided the discovery of the signal transduction cascades regulated by these proteins. In Caenorhabditis elegans, loss of function in rpm-1 causes axon overgrowth and aberrant presynaptic morphology, yet the mutant animals exhibit little behavioral deficits. Strikingly, rpm-1 mutations strongly synergize with loss of function in the presynaptic active zone assembly factors, syd-1 and syd-2, resulting in severe locomotor deficits. Here, we provide ultrastructural evidence that double mutants, between rpm-1 and syd-1 or syd-2, dramatically impair synapse formation. Taking advantage of the synthetic locomotor defects to select for genetic suppressors, previous studies have identified the DLK-1 MAP kinase cascade negatively regulated by RPM-1. We now report a comprehensive analysis of a large number of suppressor mutations of this screen. Our results highlight the functional specificity of the DLK-1 cascade in synaptogenesis. We also identified two previously uncharacterized genes. One encodes a novel protein, SUPR-1, that acts cell autonomously to antagonize RPM-1. The other affects a conserved protein ESS-2, the homolog of human ES2 or DGCR14. Loss of function in ess-2 suppresses rpm-1 only in the presence of a dlk-1 splice acceptor mutation. We show that ESS-2 acts to promote accurate mRNA splicing when the splice site is compromised. The human DGCR14/ES2 resides in a deleted chromosomal region implicated in DiGeorge syndrome, and its mutation has shown high probability as a risk factor for schizophrenia. Our findings provide the first functional evidence that this family of proteins regulate mRNA splicing in a context-specific manner. P ROPER synapse development ensures precise wiring and efficient transmission of information in the nervous system. In the presynaptic terminals, dense and organized accumulation of synaptic vesicles around the docking site called active zone is essential for rapid release of neurotransmitters (Sudhof 2012). Forward genetic screens in Caenorhabditis elegans, aided by visualization of synapse morphology using fluorescent reporters, have made important contributions to uncover conserved genes and pathways regulating presynaptic assembly (Jin and Garner 2008;Ou and Shen 2010). Many such screens have identified a common set of genes that regulate specific aspects of presynaptic differentiation in many neurons (Ackley and Jin 2004;Jin 2005;Maeder and Shen 2011). Among them are SYD-2/a-Liprin (LAR interacting protein), which has a central role in presynaptic active zone formation (Zhen and Jin 1999;Dai et al. 2006); SYD-1, a PDZ-RhoGAP protein that acts upstream of SYD-2 (Patel and Shen 2009;Hallam et al. 2002); and RPM-1, an E3 ubiquitin ligase that regulates synaptic organization (Schaefer et al. 2000;Zhen et al. 2000).Despite their strong defects in synaptic morphology, single loss-of-function (lf) mutants of rpm-1...

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supporting

confidence: 52%

Section: Ess-2 Regulates Mrna Splicingmentioning

confidence: 99%

mentioning

confidence: 99%

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Systematic Analyses of rpm-1 Suppressors Reveal Roles for ESS-2 in mRNA Splicing in Caenorhabditis elegans

2014

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“…To construct pepe1-GFP, the epe1 ϩ open reading frame was PCR amplified from genomic DNA with primers that incorporate SalI and AseI restriction sites (5Ј-ACGCGTCGACAGACTAGCACCTCTGGACCGAAG C-3Ј and 5Ј-ACGCATTAATATGGATTCCTGGCTTGAATACG-3Ј). A SalI-AseI fragment of the PCR fragment was then ligated to a SalI-NdeI fragment of pRep1-GFP (39). Diploid strains were constructed by mating AP161 and AP182 (epe1 ϩ /epe1 ϩ ), AP161 and AP2002 (epe1 ϩ /epe1-1), and AP2002 and AP2003 (epe1-1/epe1-1).…”

Section: Methodsmentioning

confidence: 99%

A Novel jmjC Domain Protein Modulates Heterochromatization in Fission Yeast

Ayoub

Noma

Isaac³

et al. 2003

Molecular and Cellular Biology

144

168

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The heterochromatin domain at the mat locus of Schizosaccharomyces pombe is bounded by the IR-L and IR-R barriers. A genetic screen for mutations that promote silencing beyond IR-L revealed a novel gene named epe1, encoding a conserved nuclear protein with a jmjC domain. Disruption of epe1 promotes continuous spreading of heterochromatin-associated histone modifications and Swi6 binding to chromatin across heterochromatic barriers. It also enhances position effect variegation at heterochromatic domains, suppresses mutations in silencing genes, and stabilizes the repressed epigenetic state at the mat locus. However, it does not enhance silencing establishment. Our analysis suggests that the jmjC domain is essential for Epe1 activity and that Epe1 counteracts transcriptional silencing by negatively affecting heterochromatin stability. Consistent with this proposition, the meiotic stability of established heterochromatin beyond IR-L is diminished by Epe1 activity, and overexpression of Epe1 disrupts heterochromatin through acetylation of H3-K9 and H3-K14 and methylation of H3-K4. Furthermore, overexpression of Epe1 elevates the rate of chromosome loss. We propose that Epe1 helps control chromatin organization by down-regulating the stability of epigenetic marks that govern heterochromatization.Epigenetic control of gene expression by clonally inherited higher-order chromatin structures accounts for diverse biological phenomena, such as dosage compensation, imprinting, and position effect variegation (PEV) (26,44,45). In addition to transcription regulation, epigenetic effects have an important impact on cellular differentiation, accurate chromosome segregation, recombination, neocentromere maintenance, and mating-type switching in yeast (reviewed in references 1, 18, 24, 25, 28, 37, and 47). Molecular models that explain chromosomal inheritance of epigenetic states assume a long-range memory mechanism that marks imprinted chromosomal domains by self-templating higher-order chromatin structures and covalent modification of DNA (20,46). Evidence for chromatin modifications in imprinted domains has been obtained through experiments that demonstrate the association of silent chromosomal regions with modified histones and chromatinassociated nonhistone proteins like Saccharomyces cerevisiae SIR3, Drosophila HP1, and Schizosaccharomyces pombe Swi6 (15,22,33,36).The mat locus of S. pombe shares an extended sequence homology with the centromeric outer repeats (cenH) and provides a useful paradigm for the highly conserved process of heterochromatin assembly and inheritance (17,18,25). Constitutive heterochromatin extends along the 15-kb mat2-K-mat3 interval that is bound on its centromere-proximal end by the REII protosilencer (Fig. 1A) (7,21,33,41). Silencing diminishes gradually at the L region as the distance from REII toward the IR-L heterochromatin barrier increases (6). IR-L, like its IR-R homologous counterpart at the centromere-distal end of the heterochromatic domain, is a distinct transition point for Swi6 associa...

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“…I identified several known transcriptional coregulators (see Table S1 in the supplemental (20,21), which is characterized by various defects of the heart, thymus, and parathyroid gland (22). DGCR14 is a nuclear protein with a coiled-coil domain (21) that is conserved in lower species, including Drosophila melanogaster (23), Caenorhabditis elegans (24), and yeast (25). Although recent studies showed that DGCR14/ES2 associates with other nuclear proteins (26) or the splicing complex (27), the role of DGCR14 in T lymphocytes is not fully understood.…”

Section: Dgcr14mentioning

confidence: 99%

DGCR14 Induces Il17a Gene Expression through the RORγ/BAZ1B/RSKS2 Complex

Takada

2015

Molecular and Cellular Biology

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The Dgcr14/Es2 gene is located in a chromosomal region the loss of which has been associated with DiGeorge syndrome, a cause of immunodeficiency, heart defects, and skeletal abnormalities. However, the role of DGCR14 protein remains to be elucidated. Here, I found that DGCR14 protein acts as a coactivator of ROR␥t in T H 17 cells. Biochemical purification of the ROR␥ coregulator complex allowed me to identify the associated DGCR14 protein by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Overexpression of Dgcr14 mRNA enhanced ROR␥t-mediated transcriptional activity and facilitated T H 17 cell differentiation. Furthermore, knockdown of Dgcr14 reduced Il17a mRNA expression. I also found that DGCR14 associated with ribosomal S6 kinase 2 (RSK2, also called RpS6ka3) and BAZ1B, both of which were recruited to the Il17a promoter during T H 17 cell differentiation. Knockdown of Baz1b or RpS6ka3 also reduced Il17a mRNA expression, and Baz1b knockdown increased transcriptional suppressive histone marks (histone H3K9me3) on the Il17a promoter. My findings showed the roles of DGCR14, RSK2, and BAZ1B in the transcriptional regulation of Il17a mRNA during T H 17 cell differentiation. Retinoid-related orphan nuclear receptor gamma (ROR␥, also called Rorc or Nr1f3) is a member of the nuclear hormone receptor (NR) superfamily. ROR␥ regulates gene transcription by binding as a monomer to specific ROR response elements (ROREs) consisting of the consensus core motif RGGTCA preceded by a 6-bp A/T-rich sequence (1). ROR␥ controls circadian rhythm, lymphocyte development, and lipid and glucose homeostasis. ROR␥ expression exhibits an oscillatory pattern (low levels during the day and maximal levels at night) in the liver, brown adipose tissue, and kidneys (2). Mice deficient in ROR␥ exhibit improved insulin sensitivity and glucose tolerance because of reduced hepatic gluconeogenesis, particularly during the daytime (3).More importantly, ROR␥ knockout mice lack peripheral and mesenteric lymph nodes and Peyer's patches (4). Furthermore, ROR␥t, which is an isoform encoded by the Rorc gene, is highly expressed in lymphocytes and acts as a key regulator in the development of T H 17 cells (5). The N-terminal region amino acid sequence of ROR␥t differs from that of ROR␥, but the DNA-and ligand-binding regions are conserved. ROR␥t knockout mice have diminished numbers of T H 17 cells and are protected against experimental autoimmune encephalomyelitis (2). Because T H 17 cells play a pivotal role in autoimmune diseases, suppression of the transcriptional activities of ROR␥t is critical for developing therapeutics for T H 17-mediated autoimmune disorders, including multiple sclerosis and rheumatoid arthritis. Recent studies have described the synthesis of inverse agonists of ROR␥ to abrogate T H 17 cell function (6-9). However, the molecular mechanism of ROR␥-dependent transcriptional regulation is not fully understood.In general, transcriptional control by NRs depends on multiprotein coregulatory complexes (10, 1...

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The Fission Yeast ES2 Homologue, Bis1, Interacts with the Ish1 Stress-responsive Nuclear Envelope Protein

Cited by 31 publications

References 49 publications

Systematic Analyses of rpm-1 Suppressors Reveal Roles for ESS-2 in mRNA Splicing in Caenorhabditis elegans

Systematic Analyses of rpm-1 Suppressors Reveal Roles for ESS-2 in mRNA Splicing in Caenorhabditis elegans

A Novel jmjC Domain Protein Modulates Heterochromatization in Fission Yeast

DGCR14 Induces Il17a Gene Expression through the RORγ/BAZ1B/RSKS2 Complex

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