Cysteine proteases have been discovered in various bloodfeeding ectoparasites. Here, we assemble the available information about the function of these peptidases and reveal their role in hematophagy and parasite development. While most of the data shed light on key proteolytic events that play a role in arthropod physiology, we also report on the association of cysteine proteases with arthropod vectorial capacity. With emphasis on ticks, specifically Ixodes ricinus, we finally propose a model about the contribution of cysteine peptidases to blood digestion and how their concerted action with other tick midgut proteases leads to the absorbance of nutrients by the midgut epithelial cells.

Laboratory of Vector Immunology Institute of Parasitology Biology Centre of the Academy of Sciences of the Czech Republic Ceske Budejovice Czech Republic

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Nava S, Guglielmone AA, Mangold AJ. An overview of systematics and evolution of ticks. Front Biosci. 2009;14:2857–2877. PubMed

de la Fuente J, Estrada-Pena A, Venzal JM, et al. Overview: Ticks as vectors of pathogens that cause disease in humans and animals. Front Biosci. 2008;13:6938–6946. PubMed

Grandjean O, Aeschlimann A. Contribution to the study of digestion in ticks: histology and fine structure of the midgut ephithelium of Ornithodorus moubata, Murray (Ixodoidea, Argasidae) Acta Trop. 1973;30:193–212. PubMed

Obenchain FD, Galun R. Physiology of Ticks. 1. Oxford: Pergamon Press; 1982.

Harrison FW, Foelix RF. Chelicerate arthropoda. New York; Chichester: Wiley; 1999.

Tarnowski BI, Coons LB. Ultrastructure of the midgut and blood meal digestion in the adult tick Dermacentor variabilis. Exp Appl Acarol. 1989;6:263–289. PubMed

Sauer JR, Hair JA. Morphology, Physiology, and Behavioral Biology of Ticks. New York: Halsted Press; 1986.

Kaufman WR. Tick-host interaction: a synthesis of current concepts. Parasitol Today. 1989;5:47–56. PubMed

Sonenshine DE. Biology of Ticks. Oxford: Oxford University Press; 1991.

Reich CI, Zorzopulos J. Boophilus microplus: characterization of larval proteases. Exp Parasitol. 1978;44:1–6. PubMed

Zorzopulos J, Reich CI, Galassi N. Boophilus microplus: characterization of larval phosphomonoesterases and isolation of subcellular fractions with high phosphatase activity. Exp Parasitol. 1978;45:128–138. PubMed

Renard G, Garcia JF, Cardoso FC, et al. Cloning and functional expression of a Boophilus microplus cathepsin L-like enzyme. Insect Biochem Mol Biol. 2000;30:1017–1026. PubMed

Renard G, Lara FA, de Cardoso FC, et al. Expression and immunolocalization of a Boophilus microplus cathepsin L-like enzyme. Insect Mol Biol. 2002;11:325–328. PubMed

Mulenga A, Sugimoto C, Onuma M. Characterization of proteolytic enzymes expressed in the midgut of Haemaphysalis longicornis. Jpn J Vet Res. 1999;46:179–184. PubMed

Mulenga A, Sugimoto C, Ingram G, et al. Molecular cloning of two Haemaphysalis longicornis cathepsin L-like cysteine proteinase genes. J Vet Med Sci. 1999;61:497–502. PubMed

Yamaji K, Tsuji N, Miyoshi T, et al. Hemoglobinase activity of a cysteine protease from the ixodid tick Haemaphysalis longicornis. Parasitol Int. 2009;58:232–237. PubMed

Tsuji N, Miyoshi T, Battsetseg B, et al. A cysteine protease is critical for Babesia spp. transmission in Haemaphysalis ticks. PLoS Pathog. 2008;4:e1000062. PubMed PMC

Sojka D, Hajdusek O, Dvorak J, et al. IrAE: an asparaginyl endopeptidase (legumain) in the gut of the hard tick Ixodes ricinus. Int J Parasitol. 2007;37:713–724. PubMed PMC

Gotz MG, James KE, Hansell E, et al. Aza-peptidyl Michael acceptors. A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolutionarily diverse pathogens. J Med Chem. 2008;51:2816–2832. PubMed

Ovat A, Muindi F, Fagan C, et al. Aza-peptidyl Michael acceptor and epoxide inhibitors--potent and selective inhibitors of Schistosoma mansoni and Ixodes ricinus legumains (asparaginyl endopeptidases) J Med Chem. 2009;52:7192–7210. PubMed

Abdul Alim M, Tsuji N, Miyoshi T, et al. Characterization of asparaginyl endopeptidase, legumain induced by blood feeding in the ixodid tick Haemaphysalis longicornis. Insect Biochem Mol Bio. 2007;37:911–922. PubMed

Alim MA, Tsuji N, Miyoshi T, et al. HlLgm2, a member of asparaginyl endopeptidases/legumains in the midgut of the ixodid tick Haemaphysalis longicornis, is involved in blood-meal digestion. J Insect Physiol. 2008;54:573–585. PubMed

Alim MA, Tsuji N, Miyoshi T, et al. Developmental stage- and organ-specific expression profiles of asparaginyl endopeptidases/legumains in the ixodid tick Haemaphysalis longicornis. J Vet Med Sci. 2008;70:1363–1366. PubMed

Alim MA, Tsuji N, Miyoshi T, et al. Legumains from the hard tick Haemaphysalis longicornis play modulatory roles in blood feeding and gut cellular remodelling and impact on embryogenesis. Int J Parasitol. 2009;39:97–107. PubMed

Boldbaatar D, Sikalizyo Sikasunge C, Battsetseg B, et al. Molecular cloning and functional characterization of an aspartic protease from the hard tick Haemaphysalis longicornis. Insect Biochem Mol Biol. 2006;36:25–36. PubMed

Sojka D, Franta Z, Horn M, et al. Profiling of proteolytic enzymes in the gut of the tick Ixodes ricinus reveals an evolutionarily conserved network of aspartic and cysteine peptidases. Parasit Vectors. 2008;1:7. PubMed PMC

Hatta T, Kazama K, Miyoshi T, et al. Identification and characterisation of a leucine aminopeptidase from the hard tick Haemaphysalis longicornis. Int J Parasitol. 2006;36:1123–1132. PubMed

Caffrey CR, McKerrow JH, Salter JP, et al. Blood ‘n’ guts: an update on schistosome digestive peptidases. Trends Parasitol. 2004;20:241–248. PubMed

Delcroix M, Sajid M, Caffrey CR, et al. A multienzyme network functions in intestinal protein digestion by a platyhelminth parasite. J Biol Chem. 2006;281:39316–39329. PubMed

Williamson AL, Brindley PJ, Knox DP, et al. Digestive proteases of blood-feeding nematodes. Trends Parasitol. 2003;19:417–423. PubMed

Anderson JM, Sonenshine DE, Valenzuela JG. Exploring the mialome of ticks: an annotated catalogue of midgut transcripts from the hard tick, Dermacentor variabilis (Acari: Ixodidae) BMC Genomics. 2008;9:552. PubMed PMC

Horn M, Nussbaumerova M, Sanda M, et al. Hemoglobin digestion in blood-feeding ticks: mapping a multipeptidase pathway by functional proteomics. Chem Biol. 2009;16:1053–1063. PubMed PMC

Grunclova L, Horn M, Vancova M, et al. Two secreted cystatins of the soft tick Ornithodoros moubata: differential expression pattern and inhibitory specificity. Biol Chem. 2006;387:1635–1644. PubMed

Fagotto F. Yolk degradation in tick eggs: I. Occurrence of a cathepsin L-like acid proteinase in yolk spheres. Arch Insect Biochem Physiol. 1990;14:217–235. PubMed

Fagotto F. Yolk degradation in tick eggs: II. Evidence that cathepsin L-like proteinase is stored as a latent, acid-activable proenzyme. Arch Insect Biochem Physiol. 1990;14:237–252. PubMed

Seixas A, Dos Santos PC, Velloso FF, et al. A Boophilus microplus vitellin-degrading cysteine endopeptidase. Parasitology. 2003;126(Pt 2):155–163. PubMed

Seixas A, Leal AT, Nascimento-Silva MC, et al. Vaccine potential of a tick vitellin-degrading enzyme (VTDCE) Vet Immunol Immunopathol. 2008;124:332–340. PubMed

Estrela A, Seixas A, Termignoni C. A cysteine endopeptidase from tick Rhipicephalus (Boophilus) microplus) larvae with vitellin digestion activity. Comp Biochem Physiol B Biochem Mol Biol. 2007;148:410–416. PubMed

Cho WL, Tsao SM, Hays AR, et al. Mosquito cathepsin B-like protease involved in embryonic degradation of vitellin is produced as a latent extraovarian precursor. J Biol Chem. 1999;274:13311–13321. PubMed

Nirmala X, Marinotti O, James AA. The accumulation of specific mRNAs following multiple blood meals in Anopheles gambiae. Insect Mol Biol. 2005;14:95–103. PubMed

Uchida K, Ohmori D, Ueno T, et al. Preoviposition activation of cathepsin-like proteinases in degenerating ovarian follicles of the mosquito Culex pipiens pallens. Dev Biol. 2001;237:68–78. PubMed

Cooper DM, Granville DJ, Lowenberger C. The insect caspases. Apoptosis. 2009;14:247–256. PubMed

Cooper DM, Pio F, Thi EP, et al. Characterization of Aedes Dredd: a novel initiator caspase from the yellow fever mosquito, Aedes aegypti. Insect Biochem Mol Biol. 2007;37:559–569. PubMed

Cooper DM, Thi EP, Chamberlain CM, et al. Aedes Dronc: a novel ecdysone-inducible caspase in the yellow fever mosquito, Aedes aegypti. Insect Mol Biol. 2007;16:563–572. PubMed

Cooper DM, Chamberlain CM, Lowenberger C. Aedes FADD: a novel death domain-containing protein required for antibacterial immunity in the yellow fever mosquito, Aedes aegypti. Insect Biochem Mol Biol. 2009;39:47–54. PubMed

Zieler H, Dvorak JA. Invasion in vitro of mosquito midgut cells by the malaria parasite proceeds by a conserved mechanism and results in death of the invaded midgut cells. Proc Natl Acad Sci U S A. 2000;97:11516–11521. PubMed PMC

Abraham EG, Islam S, Srinivasan P, et al. Analysis of the Plasmodium and Anopheles transcriptional repertoire during ookinete development and midgut invasion. J Biol Chem. 2004;279:5573–5580. PubMed

Ahmed AM, Hurd H. Immune stimulation and malaria infection impose reproductive costs in Anopheles gambiae via follicular apoptosis. Microbes Infect. 2006;8:308–315. PubMed

Yan J, Cheng Q, Li CB, Aksoy S. Molecular characterization of three gut genes from Glossina morsitans morsitans: cathepsin B, zinc-metalloprotease and zinc-carboxypeptidase. Insect Mol Biol. 2002;11:57–65. PubMed

Kollien AH, Waniek PJ, Nisbet AJ, et al. Activity and sequence characterization of two cysteine proteases in the digestive tract of the reduviid bug Triatoma infestans. Insect Mol Biol. 2004;13:569–579. PubMed

Houseman JG, Downe AER. Activity cycles and the control of four digestive proteinases in the posterior midgut of Rhodnius prolixus Stål (Hemiptera: Reduviidae) J Insect Physiol. 1983;29:141–148.

Billingsley PF, Downe AER. Ultrastructural localisation of cathepsin B in the midgut of Rhodnius prolixus Stål (Hemiptera: Reduviidae) during blood digestion. Int J Insect Morph Embryol. 1988;17:295–302.

Terra WR, Ferreira C, Garcia ES. Origin, distribution, properties and functions of the major Rhodnius prolixus midgut hydrolases. Insect Biochem. 1988;18:423–434.

Houseman JG, Downe AER. Characterization of an acidic proteinase from the posterior midgut of Rhodnius prolixus Stal (Hemiptera: Reduviidae) Insect Biochem. 1982;12:651–655.

Lopez-Ordonez T, Rodriguez MH, Hernandez-Hernandez FD. Characterization of a cDNA encoding a cathepsin L-like protein of Rhodnius prolixus. Insect Mol Biol. 2001;10:505–511. PubMed

Ferreira-DaSilva CT, Gombarovits ME, Masuda H, et al. Proteolytic activation of canatoxin, a plant toxic protein, by insect cathepsin-like enzymes. Arch Insect Biochem Physiol. 2000;44:162–171. PubMed

Carlini CR, Oliveira AE, Azambuja P, et al. Biological effects of canatoxin in different insect models: evidence for a proteolytic activation of the toxin by insect cathepsinlike enzymes. J Econ Entomol. 1997;90:340–348. PubMed

Perkins PS, Haley D, Rosenblatt R. Proteolytic enzymes in the blood-feeding parasitic copepod, Phrixocephalus cincinnatus. J Parasitol. 1997;83:6–12. PubMed

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