Plasmodium falciparum signal recognition particle components and anti-parasitic effect of ivermectin in blocking nucleo-cytoplasmic shuttling of SRP

Panchal, Manoj; Rawat, Khushboo; Kumar, Gagan; Kibria, K. M. Kaderi; Singh, Shailja; Kalamuddin,; Mohmmed, Asif; Malhotra, Pawan; Tuteja, Renu

doi:10.1038/cddis.2013.521

Cited by 59 publications

(59 citation statements)

References 38 publications

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“…Meanwhile, it has been demonstrated that even at submicromolecular levels, ivermectin inhibits the nuclear import of polypeptides of the signal recognition particle of P. falciparum (PfSRP), thereby killing the parasites. This raises the possibility that, in combination with other antimalarial agents, ivermectin could be useful in controlling malaria [70]. Although the situation is inconclusive, it reinforces recent suggestions that, if distributed strategically and frequently in MDA programmes, ivermectin could become a useful, novel malaria transmission control tool [71].…”

Section: Malariasupporting

confidence: 55%

Ivermectin: panacea for resource-poor communities?

Ōmura

Crump

2014

Trends in Parasitology

147

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Section: Malariasupporting

confidence: 55%

Ivermectin: panacea for resource-poor communities?

Ōmura

Crump

2014

Trends in Parasitology

147

View full text Add to dashboard Cite

“…Also, nuclear import is of particular importance for the replication of some virus strains, including HIV-1 [21,22] and influenza virus. Further, infection cycles of protozoan parasites partly depend on importin α/β-mediated nuclear transport [23]. Cell inflammatory responses and cell differentiation are regulated by the nuclear factor κB (NF-κB) transcription factors, whereby the p50/p65 dimer crosses the nuclear membrane in an importin α3/α4-dependent manner upon release from IκB [24].…”

Section: Relevance Of Nuclear-cytoplasmatic Transportmentioning

confidence: 99%

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

2015

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In order to pass through the nuclear pore complex, proteins larger than ∼40 kDa require specific nuclear transport receptors. Defects in nuclear-cytoplasmatic transport affect fundamental processes such as development, inflammation and oxygen sensing. The transcriptional response to O2 deficiency is controlled by hypoxia-inducible factors (HIFs). These are heterodimeric transcription factors of each ∼100-120 kDa proteins, consisting of one out of three different O2-labile α subunits (primarily HIF-1α) and a more constitutive 1β subunit. In the presence of O2, the α subunits are hydroxylated by specific prolyl-4-hydroxylase domain proteins (PHD1, PHD2, and PHD3) and an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1). The prolyl hydroxylation causes recognition by von Hippel-Lindau tumor suppressor protein (pVHL), ubiquitination, and proteasomal degradation. The activity of the oxygen sensing machinery depends on dynamic intracellular trafficking. Nuclear import of HIF-1α and HIF-1β is mainly mediated by importins α and β (α/β). HIF-1α can shuttle between nucleus and cytoplasm, while HIF-1β is permanently inside the nucleus. pVHL is localized to both compartments. Nuclear import of PHD1 relies on a nuclear localization signal (NLS) and uses the classical import pathway involving importin α/β receptors. PHD2 shows an atypical NLS, and its nuclear import does not occur via the classical pathway. PHD2-mediated hydroxylation of HIF-1α occurs predominantly in the cell nucleus. Nuclear export of PHD2 involves a nuclear export signal (NES) in the N-terminus and depends on the export receptor chromosome region maintenance 1 (CRM1). Nuclear import of PHD3 is mediated by importin α/β receptors and depends on a non-classical NLS. Specific modification of the nuclear translocation of the three PHD isoforms could provide a promising strategy for the development of new therapeutic substances to tackle major diseases.

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“…In humans it has been used to treat nematode infections such as scabies, lice and onchocerciasis (reviewed by Crump and Omura, 2011). The use of Ivermectin was also suggested as an effective and complementary strategy in malaria elimination and eradication efforts (Chaccour et al, 2013;Panchal et al, 2014). The Wagstaff group showed that Ivermectin inhibits importin α/β-dependent import with no effects on a range of other nuclear transport pathways involving members of the importin protein family.…”

Section: Introductionmentioning

confidence: 99%

The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

Kosyna

Nagel²,

Kluxen

et al. 2015

Biological Chemistry

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Hypoxia-inducible transcription factors (HIFs) regulate hundreds of genes involved in cellular adaptation to reduced oxygen availability. HIFs consist of an O2-labile α-subunit (primarily HIF-1α and HIF-2α) and a constitutive HIF-1β subunit. In normoxia the HIF-α subunit is hydroxylated by members of a family of prolyl-4-hydroxylase domain (PHD) proteins, PHD1-3, resulting in recognition by von Hippel-Lindau protein, ubiquitination and proteasomal degradation. In contrast, reduced oxygen availability inhibits PHD activity resulting in HIF-1α stabilisation and nuclear accumulation. Nuclear import of HIF-1α mainly depends on classical nuclear localisation signals (NLS) and involves importin α/β heterodimers. Recently, a specific inhibitor of nuclear import has been identified that inhibits importin α/β-dependent import with no effects on a range of other nuclear transport pathways involving members of the importin protein family. In this study we evaluated the physiological activity of this importin α/β-inhibitor (Ivermectin) in the hypoxia response pathway. Treatment with Ivermectin decreases binding activity of HIF-1α to the importin α/β-heterodimer. Moreover, HIF-1α nuclear localisation, nuclear HIF-1α protein levels, HIF-target gene expression, as well as HIF-transcriptional activity are reduced upon Ivermectin treatment. For the first time, we demonstrate the effect of specific importin α/β-inhibition on the hypoxic response on the molecular level.

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Plasmodium falciparum signal recognition particle components and anti-parasitic effect of ivermectin in blocking nucleo-cytoplasmic shuttling of SRP

Cited by 59 publications

References 38 publications

Ivermectin: panacea for resource-poor communities?

Ivermectin: panacea for resource-poor communities?

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

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