ArticlePLoS pathogens2020
The CLIP-domain serine protease CLIPC9 regulates melanization downstream of SPCLIP1, CLIPA8, and CLIPA28 in the malaria vector Anopheles gambiae.
Article in PLoS pathogens, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 58 citations in OpenAlex.
- Partial reconstitution of the prophenoloxidase activation system inProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Blood feeding, microbiota, and layered mosquito immunity: from pathway phenotypes to vector competence.Frontiers in immunology · 2026Review
- Unveiling the Multifaceted Role of HP6: A Critical Regulator of Humoral Immunity inInternational journal of molecular sciences · 2025Article
- The expanded immunoregulatory protease network in mosquitoes is governed by gene coexpression.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Mosquito immune responses to Plasmodium parasites that limit malaria transmission.Cellular and molecular life sciences : CMLS · 2025Review
- Advances in the dissection of Anopheles-Plasmodium interactions.PLoS pathogens · 2025Review
- CLIPA protein pairs function as cofactors for prophenoloxidase activation in Anopheles gambiae.Insect biochemistry and molecular biology · 2025Article
- Late sporogonic stages ofbioRxiv : the preprint server for biology · 2024Article
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- Wolbachia infection-responsive immune genes suppress Plasmodium falciparum infection in Anopheles stephensi.PLoS pathogens · 2024Article
- Immune Reactions of Vector Insects to Parasites and Pathogens.Microorganisms · 2024Review
- Higher temperature accelerates the aging-dependent weakening of the melanization immune response in mosquitoes.PLoS pathogens · 2024Article
- Late sporogonic stages ofFrontiers in cellular and infection microbiology · 2024Article
- Serine protease homolog pairs CLIPA4-A6, A4-A7Δ, and A4-A12 act as cofactors for proteolytic activation of prophenoloxidase-2 and -7 in Anopheles gambiae.Insect biochemistry and molecular biology · 2024Article
- CLIPB4 is a central node in the protease network that regulates humoral immunity in Anopheles gambiae mosquitoes.bioRxiv : the preprint server for biology · 2023Article
- CLIPB4 Is a Central Node in the Protease Network that Regulates Humoral Immunity in Anopheles gambiae Mosquitoes.Journal of innate immunity · 2023Article
- Silencing Transglutaminase GenesInsects · 2022Article
- Cleavage activation and functional comparison of Manduca sexta serine protease homologs SPH1a, SPH1b, SPH4, and SPH101 in conjunction with SPH2.Insect biochemistry and molecular biology · 2022Article
- Functional Constraints on Insect Immune System Components Govern Their Evolutionary Trajectories.Molecular biology and evolution · 2022Article
- Article
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Authors and funding
4 authors at 2 institutions in 1 country.
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Abstract
The arthropod melanization immune response is activated by extracellular protease cascades predominantly comprised of CLIP-domain serine proteases (CLIP-SPs) and serine protease homologs (CLIP-SPHs). In the malaria vector, Anopheles gambiae, the CLIP-SPHs SPCLIP1, CLIPA8, and CLIPA28 form the core of a hierarchical cascade downstream of mosquito complement that is required for microbial melanization. However, our understanding of the regulatory relationship of the CLIP-SPH cascade with the catalytic CLIP-SPs driving melanization is incomplete. Here, we report on the development of a novel screen to identify melanization pathway components based on the quantitation of melanotic mosquito excreta, eliminating the need for microdissections or hemolymph enzymatic assays. Using this screen, we identified CLIPC9 and subsequent functional analyses established that this protease is essential for the melanization of both Escherichia coli and the rodent malaria parasite Plasmodium berghei. Mechanistically, septic infection with E. coli promotes CLIPC9 cleavage and both full-length and cleaved CLIPC9 localize to this bacterium in a CLIPA8-dependent manner. The steady state level of CLIPC9 in the hemolymph is regulated by thioester-containing protein 1 (TEP1), suggesting it functions downstream of mosquito complement. In support, CLIPC9 cleavage is inhibited following SPCLIP1, CLIPA8, and CLIPA28 knockdown positioning it downstream of the CLIP-SPH cascade. Moreover, like CLIPA8 and CLIPA28, CLIPC9 processing is negatively regulated by serine protease inhibitor 2 (SRPN2). This report demonstrates how our novel excretion-based approach can be utilized to dissect the complex protease networks regulating mosquito melanization. Collectively, our findings establish that CLIPC9 is required for microbial melanization in An. gambiae and shed light on how the CLIP-SPH cascade regulates this potent immune response.
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