Genome-Wide Analysis of Histidine Repeats Reveals Their Role in the Localization of Human Proteins to the Nuclear Speckles Compartment

Salichs, Eulàlia; Ledda, Alice; Mularoni, Loris; Albà, M. Mar; Luna, Susana de la

doi:10.1371/journal.pgen.1000397

Cited by 135 publications

(151 citation statements)

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“…FoxG1 is a nuclear protein bearing a poly-histidine (His) repeat (11 His, amino acids 47-57) in its N-terminal part. As observed in our work, it has been shown that loss of DNA binding in other poly-Histidine(His)-containing nuclear proteins (such as the transcription factor MEOX2) [Salichs et al 2009] with a point mutation is associated with their localization in intranuclear speckles. Recently, Ricciardi and colleagues showed that the product of the CDKL5 gene, which is involved in the early onset seizure variant of Rett syndrome, also localizes in nuclear speckles that are involved in the pre-mRNA processing in cells [Ricciardi et al 2009].…”

Section: Discussionsupporting

confidence: 63%

A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization

et al. 2010

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ABSTRACT:The forkhead box G1 (FOXG1) gene has recently been associated with the congenital variant of Rett syndrome, and so far 17 mutations have been reported. We screened the coding region in 150 patients affected by postnatal microcephaly, and identified two mutations: the c.326C>T (p.P109L) substitution inherited from the healthy father; and the de novo c.730C>T transition, which induces the p.R244C mutation within the DNA-binding forkhead domain. This latter mutation is carried by an 8-year-old girl, who presented a phenotype reminiscent of the congenital variant of Rett syndrome. Immunofluorescence analysis of the wild-type protein revealed a homogeneous nuclear staining excluding the nucleoli, while the p.R244C mutant showed abnormal nuclear foci in a large proportion of cells, suggesting that its mislocalization may reduce and/or impair target recognition. Interestingly, this missense mutation results in a mislocalization of FoxG1 to specific nuclear foci referred to as nuclear speckles, and affects the cyclin-dependent kinase inhibitor p21 CDKN1A expression. Because CDKL5, which is involved in the early-onset variant of Rett syndrome, is also located in these speckles, we suggest that disregulation of the dynamic behaviour of nuclear speckles may functionally link these two proteins, which are both involved in atypical forms of Rett syndrome.

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Section: Discussionsupporting

confidence: 63%

A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization

et al. 2010

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“…Materials-Cloning of the following EGFP fusion protein expression vectors is described elsewhere: Sp100 (21), coilin (22), Sam68 (23), Cbx4 (24,25), Bmi-1 (26), Sc35 (27). nalaskowski@uke.uni-hamburg.de.…”

Section: Methodsmentioning

confidence: 99%

“…Overexpressed IP3KB/EGFP fusion proteins did not show this localization (data not shown). Using co-localization studies in H1299 cells, we showed that these nuclear structures are not identical with PML bodies (21), Cajal bodies (22), Sam68 nuclear bodies (23), polycomb bodies (24,25,26), or nuclear speckles (27) (data not shown). However, a co-localization with Ins(1,4,5)P 3 receptor type I and III (Fig.…”

Section: Ip3kb Is Enriched At Nuclear Invaginations Traversing Deeplymentioning

confidence: 97%

Human Inositol 1,4,5-Trisphosphate 3-Kinase Isoform B (IP3KB) Is a Nucleocytoplasmic Shuttling Protein Specifically Enriched at Cortical Actin Filaments and at Invaginations of the Nuclear Envelope

Nalaskowski

Fliegert

Ernst

et al. 2011

Journal of Biological Chemistry

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Recent studies have shown that inositol 1,4,5-trisphosphate 3-kinase isoform B (IP3KB) possesses important roles in the development of immune cells. IP3KB can be targeted to multiple cellular compartments, among them nuclear localization and binding in close proximity to the plasma membrane. The B isoform is the only IP3K that is almost ubiquitously expressed in mammalian cells. Detailed mechanisms of its targeting regulation will be important in understanding the role of Ins(1,4,5)P 3 phosphorylation on subcellular calcium signaling and compartment-specific initiation of pathways leading to regulatory active higher phosphorylated inositol phosphates. Here, we identified an exportin 1-dependent nuclear export signal ( 134 LQRELQNVQV) and characterized the amino acids responsible for nuclear localization of IP3KB ( 129 RKLR). These two targeting domains regulate the amount of nuclear IP3KB in cells. We also demonstrated that the localization of IP3KB at the plasma membrane is due to its binding to cortical actin structures. Intriguingly, all three of these targeting activities reside in one small polypeptide segment (amino acids 104 -165), which acts as a multitargeting domain (MTD). Finally, a hitherto unknown subnuclear localization of IP3KB could be demonstrated in rapidly growing H1299 cells. IP3KB is specifically enriched at nuclear invaginations extending perpendicular between the apical and basal surface of the nucleus of these flat cells. Such nuclear invaginations are known to be involved in Ins(1,4,5)P 3 -mediated Ca 2؉ signaling of the nucleus. Our findings indicate that IP3KB not only regulates cytoplasmic Ca 2؉ signals by phosphorylation of subplasmalemmal and cytoplasmic Ins(1,4,5)P 3 but may also be involved in modulating nuclear Ca 2؉ signals generated from these nuclear envelope invaginations.It is well established that the highly inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 ) 2 -specific IP3Ks remove the Ca 2ϩ -releasing second messenger Ins(1,4,5)P 3 by phosphorylating it to Ins(1,3,4,5)P 4 (1) supporting the formation of higher phosphorylated inositols in the cell (2). So far, three isoforms of IP3K, termed A (3), B (4), and C (5), have been identified in mammals. Full-length cDNAs encoding IP3K isoform B (IP3KB) were cloned from man (6) and rat (7). IP3KB was mapped to the telomeric end of human chromosome 1 (8, 9) and identified as a candidate gene in the pathogenesis of multiple sclerosis (10), Alzheimer disease (11), and malignant melanoma (12). But most importantly, IP3KB is a promising new target in immune disorders (13). Transgenic disruption of the IP3KB gene in mice causes a significant decrease in Ins(1,3,4,5)P 4 levels in thymocytes leading to a block of positive selection and consequently to a severe T cell deficiency (14). Recent studies described additional functions of IP3KB in selection and survival of B cells (15, 16), signaling of neutrophils (17), and modulation of myelopoiesis (18). In mammalian cells, multiple intracellular localizations of IP3KB, namely to the plasma membr...

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“…In addition, the threonine-proline repeats of SF3b1 (Eilbracht et al 2001) and the forkhead-associated domain in NIPP1 (Jagiello et al 2000) have also been implicated in speckle-targeting. Most recently, Salichs et al (Salichs et al 2009) performed a genomewide analysis of homopolymeric histidine tracts and identified 86 human proteins that contain stretches of five or more histidines. Of the 22 Structured illumination microscopy, using the OMX system (Applied Precision, Issaqua, Washington), of a HeLa cell expressing SC35-EYFP.…”

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confidence: 99%

Nuclear Speckles

Spector¹,

Lamond²

2010

Cold Spring Harbor Perspectives in Biology

752

720

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Nuclear speckles, also known as interchromatin granule clusters, are nuclear domains enriched in pre-mRNA splicing factors, located in the interchromatin regions of the nucleoplasm of mammalian cells. When observed by immunofluorescence microscopy, they usually appear as 20-50 irregularly shaped structures that vary in size. Speckles are dynamic structures, and their constituents can exchange continuously with the nucleoplasm and other nuclear locations, including active transcription sites. Studies on the composition, structure, and dynamics of speckles have provided an important paradigm for understanding the functional organization of the nucleus and the dynamics of the gene expression machinery.T he mammalian cell nucleus is a highly compartmentalized yet extremely dynamic organelle (reviewed in Misteli 2001a;Spector 2006;Zhao et al. 2009). Many nuclear factors are localized in distinct structures, such as speckles, paraspeckles, nucleoli, Cajal bodies, polycomb bodies, and promyelocytic leukemia bodies and show punctate staining patterns when analyzed by indirect immunofluorescence microscopy (reviewed in Lamond et al. 1998;Spector 2001;Spector 2006).In mammalian cells the pre-mRNA splicing machinery, including small nuclear ribonucleoprotein particles (snRNPs), spliceosome subunits, and other non-snRNP protein splicing factors, shows a punctate nuclear localization pattern that is usually termed "a speckled pattern" but has also been referred to as "SC35 domains (Wansink et al. 1993)" or "splicing factor compartments (Phair et al. 2000)" (Figs. 1 and 2). The first detailed description of the nuclear domains that we presently refer to as nuclear speckles was reported by Santiago Ramó n y Cajal in 1910 (Ramó n y Cajal 1910; reviewed in Lafarga et al. 2009). Ramó n y Cajal used acid aniline stains to identify structures he referred to as "grumos hialinas" (literally "translucent clumps"). The term "speckles" was first put forth in 1961 by J. Swanson Beck (Beck 1961) upon examination of rat liver sections immunolabeled with the serum of individuals with autoimmune disorders. Although the connection was not made at the time, these speckles had been identified two years earlier by Hewson Swift (Swift 1959) at the electron microscopic level and called interchromatin particles. Swift observed that these particles were not randomly distributed but that they occurred in localized "clouds," and cytochemical analysis indicated that they contained RNA (Swift 1959). However, the first link between pre-mRNA splicing and nuclear speckles or interchromatin granule clusters came from an examination of the distribution of snRNPs using anti-splicing factor-specific antibodies, demonstrating a speckled distribution pattern of snRNPs in cell nuclei (Lerner et al. 1981;Perraud et al. 1979;Spector et al. 1983).It is now clear that much of the punctate localization of splicing factors observed by immunofluorescence microscopy corresponds to the presence of these factors in nuclear speckles of variable size and irregular shape that...

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Genome-Wide Analysis of Histidine Repeats Reveals Their Role in the Localization of Human Proteins to the Nuclear Speckles Compartment

Cited by 135 publications

References 82 publications

A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization

A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization

Human Inositol 1,4,5-Trisphosphate 3-Kinase Isoform B (IP3KB) Is a Nucleocytoplasmic Shuttling Protein Specifically Enriched at Cortical Actin Filaments and at Invaginations of the Nuclear Envelope

Nuclear Speckles

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