The Leishmania donovani Ortholog of the Glycosylphosphatidylinositol Anchor Biosynthesis Cofactor PBN1 Is Essential for Host Infection

Roberts, Adam J.; Nagar, Rupa; Brandt, Cordelia; Clare, Simon; Ferguson, Michael A. J.; Wright, Gavin J.

doi:10.1128/mbio.00433-22

Cited by 3 publications

(4 citation statements)

References 67 publications

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“…GPI-anchored lipophosphoglycans (LPG) and GP63 are recognized as potential virulence factors and required for transmission ( Isnard et al., 2012 ). Consistently, a recent study showed that the loss of GPI-anchored molecules in L. donovani , induced by the ablation of LdPBN1, an enzyme required for the GPI-anchor biosynthesis, lead to the failure of infection in mouse model of visceral leishmaniasis ( Roberts et al., 2022 ). The expressive predominance of GPI-anchored surface proteins indicates that the mechanisms for transport, targeting and sorting of proteins in kinetoplastids are divergent from mammalian cells, where the most surface molecules have transmembrane domains ( Manna et al, 2014 ).…”

Section: The First Order Er Functions In Trypanosomatidssupporting

confidence: 53%

“…The protozoan Angomonas deanei, a trypanosomatid parasite of the gastrointestinal tract of insects, harbours a single endosymbiont in its cytoplasm. Recently, an elegant study by Catta-Preta and colleagues (2022), using FIB-SEM and proteomic analysis, showed a close association of symbiont bacteria with the ER, nucleus and, glycosomes of A. deanei. Multiple ER connections were found in dividing cells, mainly in the area of bacterial membrane constriction.…”

Section: The Third Order Function Of Er: Living With the Othersmentioning

confidence: 99%

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The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy

Sandes

Figueiredo²

2022

Front. Cell. Infect. Microbiol.

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The endoplasmic reticulum (ER) of higher eukaryotic cells forms an intricate membranous network that serves as the main processing facility for folding and assembling of secreted and membrane proteins. The ER is a highly dynamic organelle that interacts with other intracellular structures, as well as endosymbiotic pathogenic and non-pathogenic microorganisms. A strict ER quality control (ERQC) must work to ensure that proteins entering the ER are folded and processed correctly. Unfolded or misfolded proteins are usually identified, selected, and addressed to Endoplasmic Reticulum-Associated Degradation (ERAD) complex. Conversely, when there is a large demand for secreted proteins or ER imbalance, the accumulation of unfolded or misfolded proteins activates the Unfold Protein Response (UPR) to restore the ER homeostasis or, in the case of persistent ER stress, induces the cell death. Pathogenic trypanosomatids, such as Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp are the etiological agents of important neglected diseases. These protozoans have a complex life cycle alternating between vertebrate and invertebrate hosts. The ER of trypanosomatids, like those found in higher eukaryotes, is also specialized for secretion, and depends on the ERAD and non-canonical UPR to deal with the ER stress. Here, we reviewed the basic aspects of ER biology, organization, and quality control in trypanosomatids. We also focused on the unusual way by which T. cruzi, T. brucei, and Leishmania spp. respond to ER stress, emphasizing how these parasites’ ER-unrevealed roads might be an attractive target for chemotherapy.

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Section: The First Order Er Functions In Trypanosomatidssupporting

confidence: 53%

Section: The Third Order Function Of Er: Living With the Othersmentioning

confidence: 99%

The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy

Sandes

Figueiredo²

2022

Front. Cell. Infect. Microbiol.

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“…In humans, the Leishmania major parasite, which is known to be causal for cutaneous Leishmaniasis, is commonly transmitted in west and middle Asia by sandflies of the genus Phlebotomus but also occurs in North and South America as well as in Europe [42]. The Leishmania donovani parasite causes visceral Leishmaniasis [43]. Chowdhury et al found that 3AC administration affected the production of TNF-α, IL-12, and interferon gamma (IFN-γ) positively, which the authors called anti-leishmanial cytokines, and reduced the production of IL-10 and TGF-β, called pro-leishmanial cytokines by the authors, as well as activated NO synthesis.…”

Section: Ac As a Ship1 Inhibitor In Leishmania Major And Leishmania D...mentioning

confidence: 99%

The Functional Roles of the Src Homology 2 Domain-Containing Inositol 5-Phosphatases SHIP1 and SHIP2 in the Pathogenesis of Human Diseases

Müller,

Jücker

2024

IJMS

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The src homology 2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are two proteins involved in intracellular signaling pathways and have been linked to the pathogenesis of several diseases. Both protein paralogs are well known for their involvement in the formation of various kinds of cancer. SHIP1, which is expressed predominantly in hematopoietic cells, has been implicated as a tumor suppressor in leukemogenesis especially in myeloid leukemia, whereas SHIP2, which is expressed ubiquitously, has been implicated as an oncogene in a wider variety of cancer types and is suggested to be involved in the process of metastasis of carcinoma cells. However, there are numerous other diseases, such as inflammatory diseases as well as allergic responses, Alzheimer’s disease, and stroke, in which SHIP1 can play a role. Moreover, SHIP2 overexpression was shown to correlate with opsismodysplasia and Alzheimer’s disease, as well as metabolic diseases. The SHIP1-inhibitor 3-α-aminocholestane (3AC), and SHIP1-activators, such as AQX-435 and AQX-1125, and SHIP2-inhibitors, such as K161 and AS1949490, have been developed and partly tested in clinical trials, which indicates the importance of the SHIP-paralogs as possible targets in the therapy of those diseases. The aim of this article is to provide an overview of the current knowledge about the involvement of SHIP proteins in the pathogenesis of cancer and other human diseases and to create awareness that SHIP1 and SHIP2 are more than just tumor suppressors and oncogenes.

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“…Following this discovery, more recent studies on attenuation have utilized CRISPR to generate null mutants with high efficiency. Among the deleted targets are Centrin1 [29,34,36,71], eukaryotic translation initiation factor 4E-1 (EIF4E1) [72] and the noncatalytic component of the GPImannosyltransferase (GPI-MTI) complex [73].…”

Section: Genetic Manipulation For Selecting Live-attenuated Leishmaniamentioning

confidence: 99%

Next-Generation Leishmanization: Revisiting Molecular Targets for Selecting Genetically Engineered Live-Attenuated Leishmania

2023

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Despite decades of research devoted to finding a vaccine against leishmaniasis, we are still lacking a safe and effective vaccine for humans. Given this scenario, the search for a new prophylaxis alternative for controlling leishmaniasis should be a global priority. Inspired by leishmanization—a first generation vaccine strategy where live L. major parasites are inoculated in the skin to protect against reinfection—live-attenuated Leishmania vaccine candidates are promising alternatives due to their robust elicited protective immune response. In addition, they do not cause disease and could provide long-term protection upon challenge with a virulent strain. The discovery of a precise and easy way to perform CRISPR/Cas-based gene editing allowed the selection of safer null mutant live-attenuated Leishmania parasites obtained by gene disruption. Here, we revisited molecular targets associated with the selection of live-attenuated vaccinal strains, discussing their function, their limiting factors and the ideal candidate for the next generation of genetically engineered live-attenuated Leishmania vaccines to control leishmaniasis.

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The Leishmania donovani Ortholog of the Glycosylphosphatidylinositol Anchor Biosynthesis Cofactor PBN1 Is Essential for Host Infection

Abstract: Visceral leishmaniasis is a deadly infectious disease caused by the parasites Leishmania donovani and Leishmania infantum . It remains a major global health problem, and there is no licensed highly effective vaccine.

Cited by 3 publications

References 67 publications

The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy

The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy

The Functional Roles of the Src Homology 2 Domain-Containing Inositol 5-Phosphatases SHIP1 and SHIP2 in the Pathogenesis of Human Diseases

Next-Generation Leishmanization: Revisiting Molecular Targets for Selecting Genetically Engineered Live-Attenuated Leishmania

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