Abstract
Malaria threatens half the world's population and exacts a devastating human toll. The principal malaria vector in Africa, the mosquito Anopheles gambiae, encodes 24 members of a recently identified family of leucine-rich repeat proteins named LRIMs. Two members of this family, LRIM1 and APL1C, are crucial components of the mosquito complement-like pathway that is important for immune defense against Plasmodium parasites. LRIM1 and APL1C circulate in the hemolymph exclusively as a disulfide-bonded complex that specifically interacts with the mature form of the complement C3-like protein, TEP1. We have investigated the specificity of LRIM1/APL1C complex formation and which regions of these proteins are required for interactions with TEP1. To address these questions, we have generated a set of LRIM1 and APL1C alleles altering key conserved structural elements and assayed them in cell culture for complex formation and interaction with TEP1. Our data indicate that heterocomplex formation is an intrinsic ability of LRIM1 and APL1C and identify key homologous cysteine residues forming the intermolecular disulfide bond. We also demonstrate that the coiled-coil domain is the binding site for TEP1 but also contributes to the specificity of LRIM1/APL1C complex formation. In addition, we show that the LRIM1/APL1C complex interacts with the mature forms of three other TEP proteins, one of which, TEP3, we have characterized as a Plasmodium antagonist. We conclude that LRIM1 and APL1C contain three distinct modules: a C-terminal coiled-coil domain that can carry different TEP protein cargoes, potentially with distinct functions, a central cysteine-rich region that controls complex formation and an N-terminal leucine-rich repeat with a putative role in pathogen recognition.
Highlights
The innate immune system is the primary, and in some organisms, such as insects, the sole means of defense against infection
We demonstrate that the LRIM1/APL1C complex can interact with the mature form of three other TEPs, including TEP3, which we characterize as a novel Plasmodium antagonist
Our results suggest that the LRIM1/APL1C complex has a modular architecture in which distinct functions map to different regions
Summary
The innate immune system is the primary, and in some organisms, such as insects, the sole means of defense against infection. The majority of Plasmodium ookinetes traversing the mosquito midgut epithelium and coming into contact with the hemolymph are attacked and cleared by lysis or by encasement in a melanin capsule (melanization). Both of these reactions are triggered by binding on the parasite surface of the thioester-containing protein TEP1, a homolog of the complement factor C3 [2]. Silencing the genes that encode LRIM1, APL1C and TEP1 transforms a refractory A. gambiae strain into a susceptible strain [2,6] This triumvirate of proteins contribute to resistance against Plasmodium of the non-vector mosquito A. quadriannulatus A; their silencing renders these mosquitoes permissive vectors [11]. This interaction stabilizes this mature and reactive form of TEP1, promoting its binding to the parasite surface and preventing its reaction with self
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