Direct translocation of histone molecules across cell membranes

Hariton-Gazal, Elana; Rosenbluh, Joseph; Graessmann, A.; Gilon, Chaim; Loyter, Abraham

doi:10.1242/jcs.00757

Cited by 111 publications

(106 citation statements)

References 35 publications

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“…So far, the mechanism(s) by which histone H1 crosses the membrane are not known. Since penetration of extracellular histones through the plasma membrane into the cell has been demonstrated (Hariton-Gazal et al, 2003), it is conceivable that a similar mechanism may exist for the export of histone H1.…”

Section: Discussionmentioning

confidence: 99%

“…Interaction of histone H1 with its cell surface receptors (e.g., PSA-NCAM) may trigger signal transduction events that alter gene expression in Schwann cells and/or neurons resulting, for example, in inhibition of the expression of factors involved in neurodegeneration and/or in induction or enhancement of the expression of factors, such as cell surface receptors, growth factors, or metabolic en- zymes that generate long-lasting beneficial and positive effects on neuronal survival and neurite regrowth and thus on functional recovery and regeneration. Since histone H1 can penetrate through the plasma membrane (Hariton-Gazal et al, 2003), it is conceivable that extracellular histone H1 directly affects gene regulation after translocation into the cell and import into the nucleus. It is also conceivable that PSA may facilitate or enhance the translocation of histone H1 through the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

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Functional Role of the Interaction between Polysialic Acid and Extracellular Histone H1

Mishra¹,

Ohe²,

Schulze³

et al. 2010

J. Neurosci.

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Polysialic acid (PSA) is a large and highly negatively charged glycan that plays crucial roles in nervous system development and function in the adult. It has been suggested to facilitate cell migration, neurite outgrowth, and synaptic plasticity because its hydration volume could enhance flexibility of cell interactions. Evidence for receptors of PSA has so far been elusive. We now identified histone H1 as binding partner of PSA via a single-chain variable fragment antibody using an anti-idiotypic approach. Histone H1 directly binds to PSA as shown by ELISA. Surface biotinylation of cultured cerebellar neurons indicated an extracellular localization of histone H1. Immunostaining of live cerebellar neurons and Schwann cells confirmed that an extracellular pool of histone H1 colocalizes with PSA at the cell surface. Histone H1 was also detected in detergent-insoluble synaptosomal membrane subfractions and postsynaptic densities. When applied in vitro, histone H1 stimulated neuritogenesis, process formation and proliferation of Schwann cells, and migration of neural precursor cells via a PSA-dependent mechanism, further indicating that histone H1 is active extracellularly. These in vitro observations suggested an important functional role for the interaction between histone H1 and PSA not only for nervous system development but also for regeneration in the adult. Indeed, histone H1 improved functional recovery, axon regrowth, and precision of reinnervation of the motor branch in adult mice with femoral nerve injury. Our findings encourage investigations on the therapeutic potential of histone H1 in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functional Role of the Interaction between Polysialic Acid and Extracellular Histone H1

Mishra¹,

Ohe²,

Schulze³

et al. 2010

J. Neurosci.

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“…In effect, NLSs have been successfully conjugated to BSA to produce complexes that retain nuclear localization capacity (Goldfarb et al, 1986;Hariton-Gazal et al, 2003;Armon-Omer et al, 2004). Accordingly, BSA bearing covalently attached peptides representing the basic domain/NLS of Tat acts as a nuclear import vehicle in permeabilized cells (Krichevsky et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

BSA conjugates bearing multiple copies of the basic domain of HIV-1 Tat: Prototype for the development of multitarget inhibitors of extracellular Tat

et al. 2010

Self Cite

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a b s t r a c tThe transactivating factor (Tat) of HIV-1 is involved in AIDS progression and associated pathologies. Tat possesses a basic amino acid sequence implicated in heparan sulfate proteoglycan (HSPG)-mediated internalization, nuclear localization and transactivation by Tat and in the interaction of Tat with integrins and with the vascular endothelial growth factor receptor 2 (KDR) (kinase insert domain receptor). A BSA conjugate bearing an average of four copies of a peptide representing the basic domain/nuclear localization signal of Tat (BSA-Tat-NLS) inhibits transactivation by Tat exogenously added to cells but not by Tat endogenously produced after cell transfection with a tat cDNA, indicating that BSA-Tat-NLS does not interfere with Tat at an intracellular level. Surface plasmon resonance (SPR) experiments revealed that BSA-Tat-NLS binds to the HSPG analogue heparin. Accordingly, BSA-Tat-NLS binds to HSPGs of HL3T1 cell surface and inhibits HSPG-dependent Tat internalization. BSA-Tat-NLS retains its inhibitory potential when pre-incubated with HL3T1 cells before Tat administration, possibly by masking cell-surface HSPGs thus preventing Tat binding and internalization. SPR experiments revealed that BSA-Tat-NLS binds also to integrin ␣ v ␤ 3 and KDR. Accordingly, it inhibits pro-angiogenic endothelial cell adhesion to Tat and motogenesis. In conclusion, BSA-Tat-NLS binds/masks three different cell-surface receptors of Tat inhibiting different biological activities. These data point to BSA-Tat-NLS as a prototype for the development of Tat-antagonists endowed with a multitargeted mechanism of action.

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“…Histones have the ability to penetrate the cell membrane, even in the presence of endocytosis inhibitors (Hariton-Gazal et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Transgene expression efficiency from plasmid DNA delivered as a complex with histone H3

Kamiya

Goto

Kanda

et al. 2010

International Journal of Pharmaceutics

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The intranuclear disposition of plasmid DNA is extremely important for transgene expression. Exogenous histones have been used as carriers of plasmid DNA in histone-mediated gene delivery. In this study, the effects of exogenous histone H3 complexed with plasmid DNA on transgene expression efficiency were examined. The plasmid−histone complexes in various ratios were transfected into HeLa cells by osmotic pressure.Histone H3 suppressed transgene expression in the nucleus in a dose-dependent manner. Our results suggest that the histone-mediated gene delivery is unlikely to be useful, from the viewpoint of the intranuclear disposition.

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Direct translocation of histone molecules across cell membranes

Cited by 111 publications

References 35 publications

Functional Role of the Interaction between Polysialic Acid and Extracellular Histone H1

Functional Role of the Interaction between Polysialic Acid and Extracellular Histone H1

BSA conjugates bearing multiple copies of the basic domain of HIV-1 Tat: Prototype for the development of multitarget inhibitors of extracellular Tat

Transgene expression efficiency from plasmid DNA delivered as a complex with histone H3

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