Multiple pathways contribute to nuclear import of core histones

Mühlhäusser, Petra; Müller, Eva‐Christina; Otto, Albrecht; Kutay, Ulrike

doi:10.1093/embo-reports/kve168

Cited by 147 publications

(176 citation statements)

References 23 publications

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“…Nucleolar staining may be due to a vast excess of H1°histones after import into the nuclei of the permeabilized cells, where they may bind to ectopic sites in the nucleus, perhaps as basic proteins to the ribosomal RNA accessible in the nucleolus. This nucleolar staining has been observed previously also with other proteins, for instance with core histones (10,25) and the parathyroid hormone-related protein (33).…”

Section: Resultssupporting

confidence: 82%

“…Unlike H1 import, core histones are imported by at least five different importins, and either Imp␤ or Imp7 is capable of targeting the core histone into the nuclei of permeabilized cells on their own. Cooperativity of both importins has neither been demonstrated in binding studies nor in the in vitro import of core histones (24,25). This indicates that core histones are imported by a monomeric import receptor.…”

Section: Discussionmentioning

confidence: 99%

“…This observation and the results described above demonstrate that Imp7 does not function as an adapter for Imp␤-H1 binding in analogy to Imp␣ in Imp␤-classic NLS binding. In vitro binding assays with core histones show that each of the import receptors Imp␤, Imp5, Imp7, and transportin have the capacity to bind independently from each other (24,25). Reconstitution experiments with recombinant factors indicate that each of these factors can independently serve as an import receptor for each of the core histones.…”

Section: Fig 5 Mapping Of the Imp␤ Binding Domain In Imp7mentioning

confidence: 99%

“…Many other proteins such as ribosomal proteins (14), cyclin B (23), and core histones (19,20,24,25) are transported by monomeric import receptors, members of the importin ␤ superfamily. An exception is the nuclear transport of linker histone H1, which depends on a heterodimeric receptor consisting of two members of the importin ␤-family, namely Imp␤ and Imp7 (9).…”

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confidence: 99%

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The Requirement of H1 Histones for a Heterodimeric Nuclear Import Receptor

Bäuerle¹,

Doenecke²,

Albig³

2002

Journal of Biological Chemistry

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After synthesis in the cytoplasm, H1 histones are imported into the nucleus through an energy-dependent process that can be mediated by an importin ␤-importin 7 (Imp␤-Imp7) heterodimer. H1 histones contain two structurally different types of nuclear localization signals (NLS). The first type of NLS resides within the unstructured C-terminal domain and is rich in basic amino acids. In contrast, the highly conserved central domain of the H1 histone contains comparatively few basic amino acids but also represents a functional NLS. The competence for the nuclear import of this globular domain seems to be based on its secondary structure. Here, we show that the Imp␤-Imp7 heterodimer is the only receptor for H1 import. Furthermore, we identified the import receptors mediating the in vitro transport of different NLS of the H1 histone. Using the digitoninpermeabilized cell import assay we show that Imp␤ is the most efficient import receptor for the globular domain of H1 histones, whereas the heterodimer of Imp␤ and Imp7 is the functional receptor for the entire Cterminal domain. However, short fragments of the Cterminal domain are imported in vitro by at least four different importins, which resembles the import pathway of ribosomal proteins and core histones. In addition, we show that heterodimerization of Imp␤ with Imp7 is absolutely necessary for their proper function as an import receptor for H1 histones. These findings point to a chaperone-like function of the heterodimeric complex in addition to its function as an import receptor. It appears that the Imp␤-Imp7 heterodimer is specialized for NLS consisting of extended basic domains.Histones are the protein component of the fundamental structural unit of eukaryotic chromatin, the nucleosome. The nucleosome is composed of a core particle consisting of a histone octamer with 146 bp of DNA bent around its surface and an approximately 50-bp linker DNA connecting two adjacent core particles. This linker DNA is associated with H1 histones; hence they are termed linker histones (1). The four core histones H2A, H2B, H3, and H4 form the histone octamer. Histones are small, very basic proteins. The linker histone H1 is highly enriched in lysine, H2A and H2B are moderately lysinerich, and H3 and H4 are rich in arginine. The size of core histones varies between 11 kDa (H4) and 15 kDa (H3), whereas the H1 histones have a size of ϳ22 kDa. In mammals the class of H1 histones, the linker histones, comprises seven different subtypes, termed H1.1-H1.5, H1°, and H1t (2). Histones are composed of three domains, the very basic, unstructured C-and N-terminal domains and the hydrophobic, central globular domain, which forms the histone fold motif in the case of the core histones (3) and is involved in histone-histone interactions. During the S phase of the cell cycle, a vast amount of newly synthesized histones has to be imported into the nucleus for the formation of nucleosomes on newly replicated DNA. Thus, histones are among the most abundant substrates for nuclear transport during the...

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Section: Resultssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Fig 5 Mapping Of the Imp␤ Binding Domain In Imp7mentioning

confidence: 99%

mentioning

confidence: 99%

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The Requirement of H1 Histones for a Heterodimeric Nuclear Import Receptor

Bäuerle¹,

Doenecke²,

Albig³

2002

Journal of Biological Chemistry

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“…Coregulation of import could ensure that similar amounts of specific proteins are imported at the same time or delivered to the same place in the nucleus. To add to the complexity of determining which Kap imports a particular cargo, it has been shown that several proteins can be imported into the nucleus by more than one Kap (Rout et al, 1997;Jakel and Gorlich, 1998;Pemberton et al, 1999;Mosammaparast et al, 2001Mosammaparast et al, , 2002bMuhlhausser et al, 2001). Indeed many essential yeast nuclear proteins appear to have more than one route into the nucleus, with the preferred route being mediated by a nonessential karyopherin (Rout et al, 1997;Pemberton et al, 1999;Mosammaparast et al, 2001Mosammaparast et al, , 2002b It has been previously shown that the TATA-binding protein is imported by the karyopherin Kap114p (Morehouse et al., 1999;Pemberton et al, 1999).…”

mentioning

confidence: 99%

Nuclear Import of TFIIB Is Mediated by Kap114p, a Karyopherin with Multiple Cargo-binding Domains

Hodges

Leslie

Mosammaparast

et al. 2005

MBoC

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Nuclear import and export is mediated by an evolutionarily conserved family of soluble transport factors, the karyopherins (referred to as importins and exportins). The yeast karyopherin Kap114p has previously been shown to import histones H2A and H2B, Nap1p, and a component of the preinitiation complex (PIC), TBP. Using a proteomic approach, we have identified several potentially new cargoes for Kap114p. These cargoes include another PIC component, the general transcription factor IIB or Sua7p, which interacted directly with Kap114p. Consistent with its role as a Sua7p import factor, deletion of KAP114 led to specific mislocalization of Sua7p to the cytoplasm. An interaction between Sua7p and TBP was also detected in cytosol, raising the possibility that both Sua7p and TBP can be coimported by Kap114p. We have also shown that Kap114p possesses multiple overlapping binding sites for its partners, Sua7p, Nap1p, and H2A and H2B, as well as RanGTP and nucleoporins. In addition, we have assembled an in vitro complex containing Sua7p, Nap1p, and histones H2A and H2B, suggesting that this Kap may import several proteins simultaneously. The import of more than one cargo at a time would increase the efficiency of each import cycle and may allow the regulation of coimported cargoes. INTRODUCTIONIn eukaryotic cells the nucleocytoplasmic transport of most proteins and some RNAs is mediated by an evolutionarily conserved family of soluble transport factors, the karyopherins (also referred to as importins and exportins; reviewed in Weis, 2003;Harel and Forbes, 2004;Mosammaparast and Pemberton, 2004). After synthesis in the cytoplasm, most nuclear protein cargoes are bound by a member of the karyopherin family, through direct interaction with a nuclear localization sequence contained in the cargo protein. Transport through the nuclear pore complex occurs via transient interactions of the karyopherin with the NPC. Once in the nucleus, the karyopherin encounters a high concentration of RanGTP, which acts as a regulator of transport. Interaction of the karyopherin with RanGTP leads to dissociation of the karyopherin from its nuclear cargo (Weis, 2003;Harel and Forbes, 2004;Mosammaparast and Pemberton, 2004). In some circumstances, nuclear-binding partners of the cargo appear to also play a role in stimulating the dissociation of Kap and cargo (Senger et al., 1998;Lee and Aitchison, 1999;Pemberton et al., 1999). In yeast, there are 14 members of the karyopherin family, with Ͼ20 members in mammalian cells (Mosammaparast and Pemberton, 2004). Karyopherins appear to function in either nuclear import or nuclear export, with only two examples of a Kap that works in both directions (Weis, 2003;Harel and Forbes, 2004;Mosammaparast and Pemberton, 2004). In yeast, 11 members of the karyopherin family must import at least 1500 nuclear proteins, suggesting that each receptor must have many cargoes. To date specific transport receptor-cargo pairs have only been shown for ϳ30 cargoes; in addition the NLS sequences recognized by most Kaps is n...

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Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)‐Induced Cell Death

Chen,

Guo,

Guo

et al. 2024

Advanced Biology

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Repeat dipeptides such as poly(proline‐arginine) (polyPR) are generated from the hexanucleotide GGGGCC repeat expansions in the C9orf72 gene. These dipeptides are often considered as the genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the study, fluorescein isothiocyanate (FITC) labeled PR20 is used to investigate PR20‐induced cell death. The findings reveal that the cell death induced by PR20 is dependent on its nuclear distribution and can be blocked by a nuclear import inhibitor called importazole. Further investigation reveals that BRD4 inhibitors, such as JQ‐1 and I‐BET762, restrict cytoplasmic localization of PR20, thereby reducing its cytotoxic effect. Mechanistically, the inhibition of BRD4 leads to an increase in the expression of numerous histones, resulting in the accumulation of histones in the cytoplasm. These cytoplasmic histones associate with PR20 and limit its distribution within the nucleus. Notably, the ectopic expression of histones alone is enough to confer protection to cells treated with PR20. In addition, phenylephrine (PE) induces cellular hypertrophy and cytoplasmic distribution of histone, which also helps protect cells from PR20‐induced cell death. The research suggests that temporarily inducing the presence of cytoplasmic histones may alleviate the neurotoxic effects of dipeptide repeat proteins.

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Multiple pathways contribute to nuclear import of core histones

Cited by 147 publications

References 23 publications

The Requirement of H1 Histones for a Heterodimeric Nuclear Import Receptor

The Requirement of H1 Histones for a Heterodimeric Nuclear Import Receptor

Nuclear Import of TFIIB Is Mediated by Kap114p, a Karyopherin with Multiple Cargo-binding Domains

Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)‐Induced Cell Death

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