Thioester-containing protein 1

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Thioester-containing protein 1
Identifiers
Organism Anopheles gambia
SymbolTEP1
Entrez 2828233
RefSeq (Prot) NP_523578.1
UniProt B5AZK7
Search for
Structures Swiss-model
Domains InterPro

Thioester containing protein 1, often called TEP1 is a key component of the arthropod innate immune system. TEP1 was first identified as a key immunity gene in 2001 through functional studies on Anopheles gambiae mosquitoes. [1]

Contents

TEP1 is an antimicrobial protein which acts in a system reminiscent of the human complement pathway, which damages the cell membranes of pathogens. Studies have shown that TEP1 is structurally and functionally homologous to the human complement protein C3. [2] TEP1 is now known to be important in the resistance of Anopheles mosquitoes to Plasmodium infection, targeting the malaria parasite during its invasion into the mosquitoes body cavity. Following this discovery insect thioester containing proteins have come under increased scrutiny from the scientific community as possible targets for disease control.

TEP1 is coded for by two different alleles TEP1-S and TEP-R which are specific to susceptible and resistant mosquito populations respectively. [3]

Structure

Schematic of thioester bond: TEP1 contains a highly conserved thioester which enables the covalent labelling of parasites. Thioester.png
Schematic of thioester bond: TEP1 contains a highly conserved thioester which enables the covalent labelling of parasites.

Several crystallography studies have been used to determine the structure of TEP1. TEP1 contains a highly reactive thioester motif, which can undergo spontaneous hydrolysis. [4] The thioester group is functionally essential for TEP1 to covalently bind to the surface of invading pathogens. [4] Tep1 is a multimeric protein, meaning it is formed of multiple associated polypeptide chains. TEP1 is composed of a series of 6 macroglobulin domains, a β sheet CUB domain and an essential thioester domain, which protects the thioester motif from premature activation and hydrolysis by shielding it in the core of the molecule. [5]

Comparisons of the TEP1-S and TEP1-R gene products show that the two allelic variants encode structural differences which are particularly prevalent in the thioester domain. These differences alter both the stability of the thioester bond and the ability of TEP1 to interact with other factors in the hemolymph of the mosquito. [3] [6]

C3 homology

The structure of TEP1 and its vertebrate homologue - complement protein C3- is mostly conserved. However, there are some differences between the two molecules, for example unlike C3, TEP1 lacks an anaphylatoxin domain. The absence of this domain means that the exposed thioester bond of active TEP1 is unstable. [2] [4]

Maturation

TEP1 Maturation: TEP1-F is cleaved into TEP1-Cut. TEP1 Maturation.png
TEP1 Maturation: TEP1-F is cleaved into TEP1-Cut.

The TEP1 protein is glycosylated and secreted into the body cavity by mosquito immune cells as a 165 kDa zymogen - this inactivated form is known as TEP1-F. Upon parasite infection TEP1-F is cleaved. A protease processes the full length molecule into two fragments which remain closely associated: a ~75 kDa N-terminal and an ~85 kDa C-terminal fragment which contains the thioester bond. [7] The cleaved protein is known as TEP1-cut and represents the activated form. This mechanism is equivalent to the maturation of vertebrate pro-C3 to active C3 which occurs in the endoplasmic reticulum. [3]

Recent work has suggested the two forms of TEP1, the full TEP1-F and TEP1-cut, have separate roles. [2]

Function

TEP1 is a central component in the mosquito's immune response against invading parasites such as Plasmodium. Similar to the complement protein C3 in function, TEP1 acts as an opsonin which facilitates extensive parasite killing. [8] TEP1 covalently binds to the surface of invading pathogens, promoting phagocytosis, lysis and melanisation. [8] Through this activity TEP1 is considered an important determinant of Anopheles vector capacity. [9] TEP1 is an antimicrobial peptide which associates with APL1C/LRIM1 heterodimers to act as a pattern recognition receptor (PRR) which identifies and responds to specific patterns on pathogen cell surfaces. [2]

Studies have shown TEP1 to be a key molecule in limiting parasite numbers in mosquitoes. RNA interference (RNAi) experiments have illustrated the importance of TEP1 in clearing malaria infections in mosquitoes. RNAi knockdown of TEP1 using dsRNA resulted in a five-fold increase of Plasmodium oocysts in TEP1-S silenced mosquitoes. Knock down of TEP1-R stops parasite melanisation. [1]

Anopheles gambiae mosquito : TEP1 is a key protein in the mosquito immune response against malarial parasites Anopheles gambiae mosquito feeding 1354.p lores.jpg
Anopheles gambiae mosquito : TEP1 is a key protein in the mosquito immune response against malarial parasites

Activation

TEP1-F is secreted into the hemolymph where it is processed by a currently unknown protease into its active form – the two chained molecule TEP1-Cut. Cleavage into the cut form is followed by a change in protein structure which exposes the thioester bond. This conformational change enables TEP1 to react and covalently bind to molecules on the surface of invading pathogens. [7]

Regulation

The expression of TEP1 and other genes involved in the mosquito's anti-parasitic response is a highly regulated process. The base level of TEP1 expression is regulated by insect Toll and IMD pathways. These immune pathways limit the expression of TEP1 coding genes through NF-kB/ REL transcription factors. [10] TEP1 interacts with a heterodimeric protein complex made up of two leucine-rich repeat (LRR) domain containing proteins: leucine-rich immune molecule 1 (LRIM1) and AnophelesPlasmodium-responsive leucine-rich repeat protein 1 (APL1C). The LRR molecules have two main roles: firstly acting as control proteins which prevent the inactivation of TEP1 through hydrolysis of the thioester bond or binding to self -tissues and secondly mediate the binding of TEP1 to pathogen surfaces. [11]

Schematic illustrating the basic structures of LRIM1 and APl1C. Basic Schematic of LRIM1 and APL1C LRR proteins.png
Schematic illustrating the basic structures of LRIM1 and APl1C.

The LRIM1/APL1C heterodimer has three domains, combining the elements of a N-terminal LRR region, a pattern of cysteine residues and a C-terminal coiled-coil domain. These features determine how the complex interacts with TEP1. [11]

Complement pathway activity

The complement system was previously thought to be an exclusive feature of the immune defense of vertebrates until complement-like molecules were cloned in non-vertebrate species such as the horseshoe crab and mosquitoes. [1] The discovery of C3 like molecules in a diverse range of species suggests that the complement pathway in particular the alternative complement pathway is evolutionary ancient. [7] The TEP1 cascade most closely resembles the alternative pathway as insects do not possess adaptive immunity. [11] Therefore, unlike the classical complement pathway the TEP1 pathway is antibody independent and instead relies on the presence of factors permanently present at low levels in the hemolymph. Furthermore, both the TEP1 pathway and the alternative pathway utilise convertase mediated amplification loops to increase pathogen opsonisation.

Convergent evolution

Thioester containing protein (TEPs) appeared early in animal evolution: members of this family have been identified in diverse organisms as nematodes, insects, molluscs, fish, birds and mammals. TEP1 in Anopheles gambiae is one of the best studied of these molecules. [12] Despite close structural and functional similarities, phylogenic analysis has shown that TEP1 and other arthropod thioester proteins actually form a separate clade from vertebrate complement factors. [4] This data suggests that their complement-like activity is a likely example of parallel evolution. Further research is needed into this area. [2]

Potential use in malaria control

The characterization of TEP1 and other similar insect immune factors in insects represent new opportunities to prevent the transmission of insect vector borne diseases. Research is currently focusing on vector/parasite interactions, specifically those between Plasmodium and Anopheles mosquitoes, in order to discover novel, improved malaria prevention methods. [13] TEP1 is being explored as a possible target for genetic manipulation. A significant aim of this research is to create mosquito populations resistant to Plasmodium parasites therefore reducing the spread of malaria. [14]

Related Research Articles

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<i>Plasmodium</i> Genus of parasitic protists that can cause malaria

Plasmodium is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of Plasmodium species involve development in a blood-feeding insect host which then injects parasites into a vertebrate host during a blood meal. Parasites grow within a vertebrate body tissue before entering the bloodstream to infect red blood cells. The ensuing destruction of host red blood cells can result in malaria. During this infection, some parasites are picked up by a blood-feeding insect, continuing the life cycle.

<i>Anopheles</i> Genus of mosquito

Anopheles is a genus of mosquito first described by the German entomologist J. W. Meigen in 1818, and are known as nail mosquitoes and marsh mosquitoes. Many such mosquitoes are vectors of the parasite Plasmodium, a genus of protozoans that cause malaria in birds, reptiles, and mammals, including humans. The Anopheles gambiae mosquito is the best-known species of marsh mosquito that transmits the Plasmodium falciparum, which is a malarial parasite deadly to human beings; no other mosquito genus is a vector of human malaria.

<i>Plasmodium falciparum</i> Protozoan species of malaria parasite

Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans. The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria. P. falciparum is therefore regarded as the deadliest parasite in humans. It is also associated with the development of blood cancer and is classified as a Group 2A (probable) carcinogen.

<span class="mw-page-title-main">Classical complement pathway</span> Aspect of the immune system

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<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

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<i>Anopheles gambiae</i> Species of mosquito

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References

  1. 1 2 3 Levashina EA, Moita LF, Blandin S, Vriend G, Lagueux M, Kafatos FC (2001). "Conserved role of a complement-like protein in phagocytosis revealed by dsRNA knockout in cultured cells of the mosquito, Anopheles gambiae". Cell. 104 (5): 709–18. doi: 10.1016/S0092-8674(01)00267-7 . PMID   11257225.
  2. 1 2 3 4 5 Povelones M, Bhagavatula L, Yassine H, Tan LA, Upton LM, Osta MA, Christophides GK (2013). "The CLIP-domain serine protease homolog SPCLIP1 regulates complement recruitment to microbial surfaces in the malaria mosquito Anopheles gambiae". PLOS Pathog. 9 (9): e1003623. doi: 10.1371/journal.ppat.1003623 . PMC   3764210 . PMID   24039584.
  3. 1 2 3 Le BV, Williams M, Logarajah S, Baxter RH (2012). "Molecular basis for genetic resistance of Anopheles gambiae to Plasmodium: structural analysis of TEP1 susceptible and resistant alleles". PLOS Pathog. 8 (10): e1002958. doi: 10.1371/journal.ppat.1002958 . PMC   3464232 . PMID   23055931.
  4. 1 2 3 4 Baxter RH, Chang CI, Chelliah Y, Blandin S, Levashina EA, Deisenhofer J (2007). "Structural basis for conserved complement factor-like function in the antimalarial protein TEP1". Proc. Natl. Acad. Sci. U.S.A. 104 (28): 11615–20. Bibcode:2007PNAS..10411615B. doi: 10.1073/pnas.0704967104 . PMC   1905922 . PMID   17606907.
  5. ↑ Nonaka M (2011). "The complement C3 protein family in invertebrates" (PDF). Invertebrate Survival Journal. 8 (1): 21–32.
  6. ↑ Povelones M, Upton LM, Sala KA, Christophides GK (2011). "Structure-function analysis of the Anopheles gambiae LRIM1/APL1C complex and its interaction with complement C3-like protein TEP1". PLOS Pathog. 7 (4): e1002023. doi: 10.1371/journal.ppat.1002023 . PMC   3077365 . PMID   21533217.
  7. 1 2 3 Fraiture M, Baxter RH, Steinert S, Chelliah Y, Frolet C, Quispe-Tintaya W, Hoffmann JA, Blandin SA, Levashina EA (2009). "Two mosquito LRR proteins function as complement control factors in the TEP1-mediated killing of Plasmodium". Cell Host Microbe. 5 (3): 273–84. doi: 10.1016/j.chom.2009.01.005 . PMID   19286136.
  8. 1 2 Blandin SA, Marois E, Levashina EA (2008). "Antimalarial responses in Anopheles gambiae: from a complement-like protein to a complement-like pathway". Cell Host Microbe. 3 (6): 364–74. doi: 10.1016/j.chom.2008.05.007 . PMID   18541213.
  9. ↑ Blandin S, Shiao SH, Moita LF, Janse CJ, Waters AP, Kafatos FC, Levashina EA (2004). "Complement-like protein TEP1 is a determinant of vectorial capacity in the malaria vector Anopheles gambiae". Cell. 116 (5): 661–70. doi: 10.1016/S0092-8674(04)00173-4 . PMID   15006349.
  10. ↑ Cirimotich CM, Dong Y, Garver LS, Sim S, Dimopoulos G (2010). "Mosquito immune defenses against Plasmodium infection". Dev. Comp. Immunol. 34 (4): 387–95. doi:10.1016/j.dci.2009.12.005. PMC   3462653 . PMID   20026176.
  11. 1 2 3 Baxter RH, Steinert S, Chelliah Y, Volohonsky G, Levashina EA, Deisenhofer J (2010). "A heterodimeric complex of the LRR proteins LRIM1 and APL1C regulates complement-like immunity in Anopheles gambiae". Proc. Natl. Acad. Sci. U.S.A. 107 (39): 16817–22. Bibcode:2010PNAS..10716817B. doi: 10.1073/pnas.1010575107 . PMC   2947905 . PMID   20826443.
  12. ↑ Obbard DJ, Callister DM, Jiggins FM, Soares DC, Yan G, Little TJ (2008). "The evolution of TEP1, an exceptionally polymorphic immunity gene in Anopheles gambiae". BMC Evol. Biol. 8 (1): 274. Bibcode:2008BMCEE...8..274O. doi: 10.1186/1471-2148-8-274 . PMC   2576239 . PMID   18840262.
  13. ↑ Christophides GK, Vlachou D, Kafatos FC (2004). "Comparative and functional genomics of the innate immune system in the malaria vector Anopheles gambiae". Immunol. Rev. 198: 127–48. doi: 10.1111/j.0105-2896.2004.0127.x . PMID   15199960. S2CID   6188654.
  14. ↑ Pike AD, Cirimotich CM, Dimopoulos G (2013). "Impact of transgenic immune deployment on mosquito fitness". Ecology and Control of Vector Borne Diseases. 3: 19–33. doi:10.3920/978-90-8686-744-8_2. ISBN   978-90-8686-744-8.
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