The serine protease homolog Skanda modulates Toll-Phenoloxidase-mediated immunity in Drosophila

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ID: 327150
2026
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Abstract
Extracellular serine protease (SP) cascades are central regulators of insect innate immunity. These cascades are negatively controlled by serine protease inhibitors (serpins) and fine-tuned by serine protease homologs (SPHs), which resemble SPs but lack catalytic activity. In Drosophila, a key SP cascade-the Toll-phenoloxidase (PO) pathway-governs both the melanization response and Toll-dependent antimicrobial peptide production. This cascade is triggered by secreted pattern-recognition receptors or microbial proteases and converges on two clip-domain SPs, Persephone and Hayan, which activate the Toll ligand Spätzle via the Spätzle-Processing Enzyme (SPE) and process prophenoloxidases. Here, we characterize the SPH Skanda and uncover its role in the Toll-PO cascade. skanda is genomically clustered with hayan and persephone and is transcriptionally induced upon infection. Skanda is unusual among SPHs, containing a long serine/threonine-rich region, two clip domains, and atypical disulfide bonds. Skanda is unstable and subject to cleavage by Grass. Functional assays show that Skanda dampens activation of Hayan, and to a lesser extent Persephone, within the Toll-PO cascade. Notably, skanda-deficient flies are highly susceptible to Staphylococcus aureus despite displaying normal Toll signaling and cuticular melanization. Moreover, compound mutants lacking two members of the hayan-psh-skanda cluster reveal a hidden contribution of Skanda to Toll activation in the absence of Persephone. Together, our results identify Skanda as a modulatory SPH that fine-tunes Toll pathway activity in concert with Persephone and Hayan.
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openalex_W7204802078 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors
Journal current genetics
Year 2026
DOI
10.1093/genetics/iyag230
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