Proteomics of purified lamellocytes from Drosophila melanogaster HopT  identifies new membrane proteins and networks involved in their functions

Wan, Bin; Belghazi, Maya; Lemauf, Séverine; Poirié, Marylène; Gatti, Jean‐Luc

doi:10.1016/j.ibmb.2021.103584

Cited by 4 publications

(4 citation statements)

References 233 publications

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“…Markers of activated macrophages and lamellocytes were strikingly overrepresented among the transcripts increased in abundance in Gba1b mutants (Fig 3A ), and the corresponding proteins were overrepresented as well (Fig 3B). We found the same increased enrichment when we compared our data to a proteomic analysis of lamellocytes (Fig 3B) [62]. The data as a whole strongly suggested increased activation of immune cells in Gba1b mutants.…”

Section: Rna-seq and Proteomics Suggest Prominent Cellular Immune Act...supporting

confidence: 70%

“…In some cases, the marker list was generated from two closely related datasets (e.g., transcripts increased in abundance in both of two parasitoid infestation studies). In one case, we used a proteomic dataset by converting the proteins into gene/transcript equivalents [62]. Each marker list was finalized by eliminating any transcripts not also detected in the Gba1b RNA-Seq dataset.…”

Section: Creating Marker Listsmentioning

confidence: 99%

“…Statistical significance was tested as above. In the case of Wan et al [62], we compared a proteomic dataset directly to our head proteomics, but we also matched any protein product of a given gene rather than matching specific protein isoforms.…”

Section: Comparing Marker Lists To Gba1b Proteomic Datamentioning

confidence: 99%

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Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation

Vincow,

Thomas,

Milstein

et al. 2023

Preprint

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Mutations inGBA(glucosylceramidase beta), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for the neurodegenerative disorders Parkinson’s disease (PD) and Lewy body dementia. Recent work has suggested that neuroinflammation may be an important factor in the risk conferred byGBAmutations. We therefore systematically tested the contributions of immune-related genes to neuropathology in aDrosophilamodel of GCase deficiency. We identified target immune factors via RNA-Seq and proteomics on heads from GCase-deficient flies, which revealed both increased abundance of humoral factors and increased macrophage activation. We then manipulated the identified immune factors and measured their effect on head protein aggregates, a hallmark of neurodegenerative disease. Genetic ablation of humoral (secreted) immune factors did not suppress the development of protein aggregation. By contrast, re-expressingGba1bin activated macrophages suppressed head protein aggregation inGba1bmutants and rescued their lifespan and behavioral deficits. Moreover, reducing the GCase substrate glucosylceramide in activated macrophages also amelioratedGba1bmutant phenotypes. Taken together, our findings show that glucosylceramide accumulation due to GCase deficiency leads to macrophage activation, which in turn promotes the development of neuropathology.Author SummaryMutations in the geneGBAare the largest risk factor for developing Parkinson’s disease and Lewy body dementia, diseases in which important brain cells die. We know that the immune system can be involved in these diseases, and thatGBAmutations cause immune changes. We did experiments to learn how the immune system changes could make brain cells more likely to die. Using a fruit fly that was missing the fly version ofGBA, we found out that inappropriately activated immune cells, but not secreted immune proteins, were important in the development of brain problems. We also learned that the abnormal activation was triggered by the lack ofGBAfunction in the immune cells, not by signals from the brain or other parts of the body. We would like to find out next whether the immune cells get inside the brain or cause harm from a distance. What we learned matters because it could help us prevent or cure brain diseases associated withGBAmutations. Treating the abnormal activation of immune cells in people with these mutations might help prevent damage to the brain.

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Section: Rna-seq and Proteomics Suggest Prominent Cellular Immune Act...supporting

confidence: 70%

Section: Creating Marker Listsmentioning

confidence: 99%

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Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation

Vincow,

Thomas,

Milstein

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Finally, to further pursue the question regarding the identity of encapsulating mechanisms, we compared the molecular make-up of encapsulating blood cells in different species of Drosophilidae . Specifically, based on previous studies, we carried out a comparison of the lamellocyte-specific genes and proteins that were characterized in D. melanogaster [ 35 , 36 , 37 , 38 , 39 , 40 ] and tested if these were also enriched in MGHs and/or activated plasmatocytes of D. ananassae . We found that 61 and 33 D. melanogaster lamellocyte-specific genes were also selectively expressed in D. ananassae MGHs and in the activated plasmatocytes, respectively (online suppl.…”

Section: Resultsmentioning

confidence: 99%

Broad Ultrastructural and Transcriptomic Changes Underlie the Multinucleated Giant Hemocyte Mediated Innate Immune Response against Parasitoids

et al. 2021

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Multinucleated giant hemocytes (MGHs) represent a novel type of blood cell in insects that participate in a highly efficient immune response against parasitoid wasps involving isolation and killing of the parasite. Previously, we showed that circulating MGHs have high motility and the interaction with the parasitoid rapidly triggers encapsulation. However, structural and molecular mechanisms behind these processes remained elusive. Here, we used detailed ultrastructural analysis and live cell imaging of MGHs to study encapsulation in <i>Drosophila ananassae</i> after parasitoid wasp infection. We found dynamic structural changes, mainly driven by the formation of diverse vesicular systems and newly developed complex intracytoplasmic membrane structures, and abundant generation of giant cell exosomes in MGHs. In addition, we used RNA sequencing to study the transcriptomic profile of MGHs and activated plasmatocytes 72 h after infection, as well as the uninduced blood cells. This revealed that differentiation of MGHs was accompanied by broad changes in gene expression. Consistent with the observed structural changes, transcripts related to vesicular function, cytoskeletal organization, and adhesion were enriched in MGHs. In addition, several orphan genes encoding for hemolysin-like proteins, pore-forming toxins of prokaryotic origin, were expressed at high level, which may be important for parasitoid elimination. Our results reveal coordinated molecular and structural changes in the course of MGH differentiation and parasitoid encapsulation, providing a mechanistic model for a powerful innate immune response.

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Genetics

Beukeboom,

Zwaan,

Mayes

et al. 2023

Jervis's Insects as Natural Enemies: Practical Perspectives

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Proteomics of purified lamellocytes from Drosophila melanogaster HopT identifies new membrane proteins and networks involved in their functions

Cited by 4 publications

References 233 publications

Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation

Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation

Broad Ultrastructural and Transcriptomic Changes Underlie the Multinucleated Giant Hemocyte Mediated Innate Immune Response against Parasitoids

Genetics

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