The serpin Spn5 is essential for wing expansion in Drosophila melanogaster

Charron, Yves; Madani, Rime; Combepine, Chantal; Gajdosik, Vincent; Hwu, Y.; Margaritondo, G.; Vassalli, Jean‐Dominique

doi:10.1387/ijdb.072419yc

Cited by 16 publications

(10 citation statements)

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“…This corroborates a high conservation of the regulatory role of serpins among different species, and their functional versatility suggesting an evolutionary adaptation to confront different and novel proteases [ 50 ]. Processes such as host innate immune response regulation [ 51 , 52 ]; tick defences [ 49 , 53 ]; hemolymph coagulation cascade [ 54 ] and tick development [ 55 , 56 ] are regulated by serine protease inhibitors. In ixodidae , serpins are an extensive protein family with an important role at the physiological level, particularly during the parasitic periods of attachment and blood feeding [ 14 , 21 - 23 , 26 , 28 , 32 , 35 , 52 , 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Rhipicephalus microplus serine protease inhibitor family: annotation, expression and functional characterisation assessment

Rodriguez-Valle

Kurscheid²,

Lew-Tabor

2015

Parasites & Vectors

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BackgroundRhipicephalus (Boophilus) microplus evades the host’s haemostatic system through a complex protein array secreted into tick saliva. Serine protease inhibitors (serpins) conform an important component of saliva which are represented by a large protease inhibitor family in Ixodidae. These secreted and non-secreted inhibitors modulate diverse and essential proteases involved in different physiological processes.MethodsThe identification of R. microplus serpin sequences was performed through a web-based bioinformatics environment called Yabi. The database search was conducted on BmiGi V1, BmiGi V2.1, five SSH libraries, Australian tick transcriptome libraries and RmiTR V1 using bioinformatics methods. Semi quantitative PCR was carried out using different adult tissues and tick development stages. The cDNA of four identified R. microplus serpins were cloned and expressed in Pichia pastoris in order to determine biological targets of these serpins utilising protease inhibition assays.ResultsA total of four out of twenty-two serpins identified in our analysis are new R. microplus serpins which were named as RmS-19 to RmS-22. The analyses of DNA and predicted amino acid sequences showed high conservation of the R. microplus serpin sequences. The expression data suggested ubiquitous expression of RmS except for RmS-6 and RmS-14 that were expressed only in nymphs and adult female ovaries, respectively. RmS-19, and -20 were expressed in all tissues samples analysed showing their important role in both parasitic and non-parasitic stages of R. microplus development. RmS-21 was not detected in ovaries and RmS-22 was not identified in ovary and nymph samples but were expressed in the rest of the samples analysed. A total of four expressed recombinant serpins showed protease specific inhibition for Chymotrypsin (RmS-1 and RmS-6), Chymotrypsin / Elastase (RmS-3) and Thrombin (RmS-15).ConclusionThis study constitutes an important contribution and improvement to the knowledge about the physiologic role of R. microplus serpins during the host-tick interaction.

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Section: Discussionmentioning

confidence: 99%

Rhipicephalus microplus serine protease inhibitor family: annotation, expression and functional characterisation assessment

Rodriguez-Valle

Kurscheid²,

Lew-Tabor

2015

Parasites & Vectors

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“…Spn5 is a member of the serine protease inhibitor superfamily and has been shown to negatively regulate the Toll pathway by inhibiting proteolytic activation of Toll [19][20][21]. Similar to other immune-related serpins, Spn5 has an N-terminal secretion signal sequence and is therefore secreted to the extracellular space [22]. Importantly, elimination of scrib clones was also suppressed when Spn5 was knocked down in scrib clones (Figures S1B-S1D), suggesting that Spn5 protein in the extracellular space is produced not only from wild-type cells but also from scrib cells.…”

Section: Eld-5 Encodes a Secreted Serpin Spn5mentioning

confidence: 99%

Serpin Facilitates Tumor-Suppressive Cell Competition by Blocking Toll-Mediated Yki Activation in Drosophila

et al. 2018

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Normal epithelial tissue exerts an intrinsic tumor-suppressive effect against oncogenically transformed cells. In Drosophila imaginal epithelium, clones of oncogenic polarity-deficient cells mutant for scribble (scrib) or discs large (dlg) are eliminated by cell competition when surrounded by wild-type cells. Here, through a genetic screen in Drosophila, we identify Serpin5 (Spn5), a secreted negative regulator of Toll signaling, as a crucial factor for epithelial cells to eliminate scrib mutant clones from epithelium. Downregulation of Spn5 in wild-type cells leads to elevation of Toll signaling in neighboring scrib cells. Strikingly, forced activation of Toll signaling or Toll-related receptor (TRR) signaling in scrib clones transforms scrib cells from losers to supercompetitors, resulting in tumorous overgrowth of mutant clones. Mechanistically, Toll activation in scrib clones leads to c-Jun N-terminal kinase (JNK) activation and F-actin accumulation, which cause strong activation of the Hippo pathway effector Yorkie that blocks cell death and promotes cell proliferation. Our data suggest that Spn5 secreted from normal epithelial cells acts as a component of the extracellular surveillance system that facilitates elimination of pre-malignant cells from epithelium.

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“…Like most other Drosophila serpins, Spn5 contains a putative N-terminal secretion signal and is widely expressed in many tissues (28). However, the exact function of Spn5 and its secretory properties have not been characterized.…”

Section: Overexpression Of Spn5 Suppresses the Chmp2b Intron5 Phenotypementioning

confidence: 99%

Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia

Ahmad

Sweeney

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

104

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Frontotemporal dementia (FTD) is the most common form of dementia before 60 years of age. Rare pathogenic mutations in CHMP2B, which encodes a component of the endosomal sorting complex required for transport (ESCRT-III), are associated with FTD linked to chromosome 3 (FTD3). Animal models of FTD3 have not yet been reported, and what signaling pathways are misregulated by mutant CHMP2B in vivo is unknown. Here we report the establishment of a Drosophila model of FTD3 and show the genetic interactions between mutant CHMP2B and other components of ESCRT. Through an unbiased genome-wide screen, we identified 29 modifier loci and found that serpin5 (Spn5), a largely uncharacterized serine protease inhibitor, suppresses the melanization phenotype induced by mutant CHMP2B in the fly eye. We also found that Spn5 is a negative regulator of the Toll pathway and functions extracellularly, likely by blocking the proteolytic activation of Spaetzle, the Toll receptor ligand. Moreover, Spn5 inhibited activation of the Toll pathway by mutant CHMP2B. Our findings identify Spn5 as a regulator of the Toll pathway and CHMP2B toxicity and show that the Toll pathway is a major signaling pathway misregulated by mutant CHMP2B in vivo. This fly model will be useful to further dissect genetic pathways that are potentially relevant to the pathogenesis and treatment of FTD.Drosophila ͉ endosomal sorting complex required for transport (ESCRT) ͉ neurodegeneration ͉ modifier screen F rontotemporal dementia (FTD), a major clinical syndrome of frontotemporal lobar degeneration (FTLD), is a progressive neurodegenerative condition associated with focal atrophy of the frontal and/or temporal lobes (1, 2). Although FTD is the most common form of senile dementia in people under 60 years of age, the molecular pathogenesis remains poorly understood (3). In some FTD brains, tau neurofibrillary tangles are present in diseased neurons, and some tau mutations are indeed pathogenic (4, 5). Several new genes have been implicated in FTD with tau-negative pathology, including those encoding valosin-containing protein (VCP) (6), CHMP2B (7), progranulin (8, 9), and TDP-43 (10, 11). The molecular pathways affected by these mutations and how they contribute to disease progression remain unclear.Although dominantly inherited CHMP2B mutations associated with FTD linked to chromosome 3 (FTD3) are rare (7,12,13), studies of CHMP2B neurotoxicity in cell culture models have been informative. CHMP2B is the ortholog of the yeast protein Vps2, a component of the endosomal sorting complex required for transport (ESCRT-III), which is involved in the biogenesis of multivesicular bodies and other biological processes (14). In undifferentiated PC12 cells, ectopic overexpression of CHMP2B Intron5 , a mutant form of CHMP2B missing 35 aa at the C terminus, led to the accumulation of vesicular structures (7). In cultured rodent cortical neurons and other cell types, CHMP2B Intron5 caused dendritic retraction, autophagosome accumulation, and neuronal cell loss (15,16). At the mol...

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The serpin Spn5 is essential for wing expansion in Drosophila melanogaster

Cited by 16 publications

References 54 publications

Rhipicephalus microplus serine protease inhibitor family: annotation, expression and functional characterisation assessment

Rhipicephalus microplus serine protease inhibitor family: annotation, expression and functional characterisation assessment

Serpin Facilitates Tumor-Suppressive Cell Competition by Blocking Toll-Mediated Yki Activation in Drosophila

Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia

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