ORCID Profile
0000-0002-8072-8557
Current Organisations
Forschungszentrum Jülich
,
Universidade de Lisboa
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Publisher: International Union of Crystallography (IUCr)
Date: 31-03-2010
Publisher: Elsevier BV
Date: 07-2004
Publisher: Springer Science and Business Media LLC
Date: 19-11-2020
DOI: 10.1038/S42003-020-01422-1
Abstract: The malaria parasite Plasmodium obligatorily infects and replicates inside hepatocytes surrounded by a parasitophorous vacuole membrane (PVM), which is decorated by the host-cell derived autophagy protein LC3. We have previously shown that the parasite-derived, PVM-resident protein UIS3 sequesters LC3 to avoid parasite elimination by autophagy from hepatocytes. Here we show that a small molecule capable of disrupting this interaction triggers parasite elimination in a host cell autophagy-dependent manner. Molecular docking analysis of more than 20 million compounds combined with a phenotypic screen identified one molecule, C4 (4-{[4-(4-{5-[3-(trifluoromethyl) phenyl]-1,2,4-oxadiazol-3-yl}benzyl)piperazino]carbonyl}benzonitrile), capable of impairing infection. Using biophysical assays, we established that this impairment is due to the ability of C4 to disrupt UIS3–LC3 interaction, thus inhibiting the parasite’s ability to evade the host autophagy response. C4 impacts infection in autophagy-sufficient cells without harming the normal autophagy pathway of the host cell. This study, by revealing the disruption of a critical host–parasite interaction without affecting the host’s normal function, uncovers an efficient anti-malarial strategy to prevent this deadly disease.
Publisher: Springer Science and Business Media LLC
Date: 06-11-2020
DOI: 10.1038/S41467-020-19492-4
Abstract: Plasmodium parasites possess a translocon that exports parasite proteins into the infected erythrocyte. Although the translocon components are also expressed during the mosquito and liver stage of infection, their function remains unexplored. Here, using a combination of genetic and chemical assays, we show that the translocon component Exported Protein 2 (EXP2) is critical for invasion of hepatocytes. EXP2 is a pore-forming protein that is secreted from the sporozoite upon contact with the host cell milieu. EXP2-deficient sporozoites are impaired in invasion, which can be rescued by the exogenous administration of recombinant EXP2 and alpha-hemolysin (an S. aureus pore-forming protein), as well as by acid sphingomyelinase. The latter, together with the negative impact of chemical and genetic inhibition of acid sphingomyelinase on invasion, reveals that EXP2 pore-forming activity induces hepatocyte membrane repair, which plays a key role in parasite invasion. Overall, our findings establish a novel and critical function for EXP2 that leads to an active participation of the host cell in Plasmodium sporozoite invasion, challenging the current view of the establishment of liver stage infection.
Publisher: MDPI AG
Date: 10-01-2022
DOI: 10.3390/NCRNA8010003
Abstract: We are delighted to share with you our seventh Journal Club and highlight some of the most interesting papers published recently [...]
Publisher: International Union of Crystallography (IUCr)
Date: 26-08-2006
Publisher: Cold Spring Harbor Laboratory
Date: 03-02-2023
DOI: 10.1101/2023.02.03.526922
Abstract: Human gene research studies that describe wrongly identified nucleotide sequence reagents have been mostly identified in journals of low to moderate impact factor, where unreliable findings could be considered to have limited influence on future research. This study examined whether papers describing wrongly identified nucleotide sequences are also published in high impact factor cancer research journals. We manually verified nucleotide sequence identities in original Molecular Cancer articles published in 2014, 2016, 2018 and 2020, including nucleotide sequence reagents that were claimed to target circRNAs. Using keywords identified in problematic 2018 and 2020 Molecular Cancer papers, we also verified nucleotide sequence identities in 2020 Oncogene papers that studied miRNA(s) and/or circRNA(s). Overall, 3.8% (253/6,647) and 4.3% (50/1,165) nucleotide sequences that were verified in Molecular Cancer and Oncogene papers, respectively, were found to be wrongly identified. These wrongly identified nucleotide sequences were distributed across 18% (92/500) original Molecular Cancer papers, including 38% Molecular Cancer papers from 2020, and 40% (21/52) selected Oncogene papers from 2020. Original papers with wrongly identified nucleotide sequences were therefore unexpectedly frequent in two high impact factor cancer research journals, highlighting the risks of employing journal impact factors or citations as proxies for research quality.
Location: Portugal
Start Date: 2018
End Date: 2021
Funder: Fundação para a Ciência e a Tecnologia
View Funded Activity