The mosquito melanization response requires hierarchical activation of non-catalytic clip domain serine protease homologs

Autoři: Layla El Moussawi aff001;  Johnny Nakhleh aff001;  Layla Kamareddine aff002;  Mike A. Osta aff001
Působiště autorů: Department of Biology, American University of Beirut, Beirut, Lebanon aff001;  Department of Biomedical Sciences, Qatar University, Doha, Qatar aff002
Vyšlo v časopise: The mosquito melanization response requires hierarchical activation of non-catalytic clip domain serine protease homologs. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008194
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008194


Serine protease cascades regulate important insect immune responses namely melanization and Toll pathway activation. An important component of these cascades are clip-domain serine protease homologs (cSPHs), which are non-catalytic, but essential for activating the enzyme prophenoloxidase (PPO) in the melanization response during septic infections. The activation of cSPHs requires their proteolytic cleavage, yet factors that control their activation and the complexity of their interactions within these cascades remain unclear. Here, we report the identification of CLIPA28 as a novel immune-related cSPH in the malaria vector Anopheles gambiae. Functional genetic analysis using RNA interference (RNAi) revealed that CLIPA28 is essential for the melanization of Plasmodium berghei parasites in refractory mosquitoes, and for mosquito resistance to fungal infections. We further show, using combined biochemical and genetic approaches, that CLIPA28 is member of a network of at least four cSPHs, whereby members are activated in a hierarchical manner following septic infections. Depletion of the complement-like protein TEP1 abolished the activation of this network after septic infections, whereas, depletion of the serine protease inhibitor 2 (SRPN2) triggered enhanced network activation, even in naïve mosquitoes, culminating in a dramatic reduction in cSPHs hemolymph levels, which paralleled that of PPO. Our data suggest that cSPHs are engaged in complex and multilayered interactions within serine protease cascades that regulate melanization, and identify TEP1 and SRPN2 as two master regulators of the cSPH network.

Klíčová slova:

Immune response – Malarial parasites – Mosquitoes – Parasitic diseases – Plasmodium – Regulator genes – Serine proteases – Staphylococcus aureus


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