Peptidylarginine Deiminase (PAD) and Post-Translational Protein Deimination-Novel Insights into Alveolata Metabolism, Epigenetic Regulation and Host-Pathogen Interactions

Overview

Journal Biology (Basel)

Publisher MDPI

Specialty Biology

Date 2021 Mar 3

PMID 33653015

Citations 3

Authors

Arni Kristmundsson

Asthildur Erlingsdottir

Sigrun Lange

Affiliations

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Abstract

The alveolates (Superphylum Alveolata) comprise a group of primarily single-celled eukaryotes that have adopted extremely diverse modes of nutrition, such as predation, photoautotrophy and parasitism. The alveolates consists of several major phyla including the apicomplexans, a large group of unicellular, spore forming obligate intracellular parasites, and chromerids, which are believed to be the phototrophic ancestors of the parasitic apicomplexans. Molecular pathways involved in Alveolata host-pathogen interactions, epigenetic regulation and metabolism in parasite development remain to be fully understood. Peptidylarginine deiminases (PADs) are a phylogenetically conserved enzyme family which causes post-translational protein deimination, affecting protein function through the conversion of arginine to citrulline in a wide range of target proteins, contributing to protein moonlighting in physiological and pathological processes. The identification of deiminated protein targets in alveolate parasites may therefore provide novel insight into pathogen survival and host-pathogen interactions. The current study assessed PAD homologues and deiminated protein profiles of two alveolate parasites, (Chromerida) and (Apicomplexa). Histological analysis verified strong cytoplasmic PAD expression in both Alveolates, detected deiminated proteins in nuclear and cytoplasmic compartments of the alveolate parasites and verified the presence of citrullinated histone H3 in Alveolata nucleus, indicating roles in epigenetic regulation. Histone H3 citrullination was also found significantly elevated in the host tissue, indicative of neutrophil extracellular trap formation, a host-defence mechanism against a range of pathogens, particularly those that are too large for phagocytosis. Proteomic analysis of deiminated proteins from both Alveolata identified GO and KEGG pathways strongly relating to metabolic and genetic regulation, with some species-specific differences between the apicomplexan and the chromerid. Our findings provide novel insights into roles for the conserved PAD/ADI enzyme family in the regulation of metabolic and epigenetic pathways in alveolate parasites, possibly also relating to their life cycle and host-pathogen interactions.

Citing Articles

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DAlessio S, Buckley K, Kraev I, Hayes P, Lange S Biology (Basel). 2021; 10(9).

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Effect of Peptidylarginine Deiminase 4 on Endothelial Progenitor Cell Function in Peripheral Arterial Disease.

Pan J, Liu W, Chen Y, Zhang C, Lin C Evid Based Complement Alternat Med. 2021; 2021:7550693.

PMID: 34349829 PMC: 8328689. DOI: 10.1155/2021/7550693.

References

Criscitiello M, Kraev I, Petersen L, Lange S . Deimination Protein Profiles in Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation. Front Immunol. 2020; 11:651. PMC: 7198796. DOI: 10.3389/fimmu.2020.00651. View

Mathur V, Kwong W, Husnik F, Irwin N, Kristmundsson A, Gestal C . Phylogenomics Identifies a New Major Subgroup of Apicomplexans, Marosporida class nov., with Extreme Apicoplast Genome Reduction. Genome Biol Evol. 2021; 13(2). PMC: 7875001. DOI: 10.1093/gbe/evaa244. View

Villagra-Blanco R, Silva L, Conejeros I, Taubert A, Hermosilla C . Pinniped- and Cetacean-Derived ETosis Contributes to Combating Emerging Apicomplexan Parasites (, ) Circulating in Marine Environments. Biology (Basel). 2019; 8(1). PMC: 6466332. DOI: 10.3390/biology8010012. View

Mathur V, Kolisko M, Hehenberger E, Irwin N, Leander B, Kristmundsson A . Multiple Independent Origins of Apicomplexan-Like Parasites. Curr Biol. 2019; 29(17):2936-2941.e5. DOI: 10.1016/j.cub.2019.07.019. View

Magnadottir B, Uysal-Onganer P, Kraev I, Svansson V, Hayes P, Lange S . Deiminated proteins and extracellular vesicles - Novel serum biomarkers in whales and orca. Comp Biochem Physiol Part D Genomics Proteomics. 2020; 34:100676. DOI: 10.1016/j.cbd.2020.100676. View

Vossenaar E, Zendman A, van Venrooij W, Pruijn G . PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays. 2003; 25(11):1106-18. DOI: 10.1002/bies.10357. View

Bowden T, Kraev I, Lange S . Extracellular vesicles and post-translational protein deimination signatures in haemolymph of the American lobster (Homarus americanus). Fish Shellfish Immunol. 2020; 106:79-102. DOI: 10.1016/j.fsi.2020.06.053. View

Spielman A, Wilson M, Levine J, Piesman J . Ecology of Ixodes dammini-borne human babesiosis and Lyme disease. Annu Rev Entomol. 1985; 30:439-60. DOI: 10.1146/annurev.en.30.010185.002255. View

Obornik M, Modry D, Lukes M, cernotikova-Stribrna E, Cihlar J, Tesarova M . Morphology, ultrastructure and life cycle of Vitrella brassicaformis n. sp., n. gen., a novel chromerid from the Great Barrier Reef. Protist. 2011; 163(2):306-23. DOI: 10.1016/j.protis.2011.09.001. View

10.

Bartosova-Sojkova P, Oppenheim R, Soldati-Favre D, Lukes J . Epicellular Apicomplexans: Parasites "On the Way In". PLoS Pathog. 2015; 11(9):e1005080. PMC: 4581633. DOI: 10.1371/journal.ppat.1005080. View

11.

Jeffers V, Tampaki Z, Kim K, Sullivan Jr W . A latent ability to persist: differentiation in Toxoplasma gondii. Cell Mol Life Sci. 2018; 75(13):2355-2373. PMC: 5988958. DOI: 10.1007/s00018-018-2808-x. View

12.

Magnadottir B, Uysal-Onganer P, Kraev I, Svansson V, Skirnisson K, Lange S . Deiminated proteins and extracellular vesicles as novel biomarkers in pinnipeds: Grey seal (Halichoerus gryptus) and harbour seal (Phoca vitulina). Biochimie. 2020; 171-172:79-90. DOI: 10.1016/j.biochi.2020.02.017. View

13.

Mondal S, Thompson P . Protein Arginine Deiminases (PADs): Biochemistry and Chemical Biology of Protein Citrullination. Acc Chem Res. 2019; 52(3):818-832. PMC: 6443095. DOI: 10.1021/acs.accounts.9b00024. View

14.

Li P, Li M, Lindberg M, Kennett M, Xiong N, Wang Y . PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med. 2010; 207(9):1853-62. PMC: 2931169. DOI: 10.1084/jem.20100239. View

15.

Guimaraes-Costa A, Nascimento M, Froment G, Soares R, Morgado F, Conceicao-Silva F . Leishmania amazonensis promastigotes induce and are killed by neutrophil extracellular traps. Proc Natl Acad Sci U S A. 2009; 106(16):6748-53. PMC: 2672475. DOI: 10.1073/pnas.0900226106. View

16.

Magnadottir B, Hayes P, Hristova M, Bragason B, Nicholas A, Dodds A . Post-translational protein deimination in cod (Gadus morhua L.) ontogeny novel roles in tissue remodelling and mucosal immune defences?. Dev Comp Immunol. 2018; 87:157-170. DOI: 10.1016/j.dci.2018.06.006. View

17.

El-Sayed A, Shindia A, AbouZaid A, M Yassin A, Ali G, Sitohy M . Biochemical characterization of peptidylarginine deiminase-like orthologs from thermotolerant Emericella dentata and Aspergillus nidulans. Enzyme Microb Technol. 2019; 124:41-53. DOI: 10.1016/j.enzmictec.2019.02.004. View

18.

Wright P, Bolling L, Calvert M, Sarmento O, Berkeley E, Shea M . ePAD, an oocyte and early embryo-abundant peptidylarginine deiminase-like protein that localizes to egg cytoplasmic sheets. Dev Biol. 2003; 256(1):73-88. DOI: 10.1016/s0012-1606(02)00126-4. View

19.

Stobernack T, du Teil Espina M, Mulder L, Palma Medina L, Piebenga D, Gabarrini G . A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses. mBio. 2018; 9(5). PMC: 6212822. DOI: 10.1128/mBio.01704-18. View

20.

Gavinho B, Sabatke B, Feijoli V, Volpato Rossi I, da Silva J, Evans-Osses I . Peptidylarginine Deiminase Inhibition Abolishes the Production of Large Extracellular Vesicles From , Affecting Host-Pathogen Interactions by Hindering Adhesion to Host Cells. Front Cell Infect Microbiol. 2020; 10:417. PMC: 7539837. DOI: 10.3389/fcimb.2020.00417. View