Abstract
Key message
A key module, secretory component (SC), was efficiently expressed in Arabidopsis thaliana. The plant-based SC and immunoglobulin A of animal or plant origin formed secretory IgA that maintains antigen-binding activity.
Abstract
Plant expression systems are suitable for scalable and cost-effective production of biologics. Secretory immunoglobulin A (SIgA) will be useful as a therapeutic antibody against mucosal pathogens. SIgA is equipped with a secretory component (SC), which assists the performance of SIgA on the mucosal surface. Here we produced SC using a plant expression system and formed SIgA with dimeric IgAs produced by mouse cells as well as by whole plants. To increase the expression level, an endoplasmic reticulum retention signal peptide, KDEL (Lys-Asp-Glu-Leu), was added to mouse SC (SC-KDEL). The SC-KDEL cDNA was inserted into a binary vector with a translational enhancer and an efficient terminator. The SC-KDEL transgenic Arabidopsis thaliana produced SC-KDEL at the level of 2.7% of total leaf proteins. In vitro reaction of the plant-derived SC-KDEL with mouse dimeric monoclonal IgAs resulted in the formation of SIgA. When reacted with Shiga toxin 1 (Stx1)-specific ones, the antigen-binding activity was maintained. When an A. thaliana plant expressing SC-KDEL was crossed with one expressing dimeric IgA specific for Stx1, the plant-based SIgA exhibited antigen-binding activity. Leaf extracts of the crossbred transgenic plants neutralized Stx1 cytotoxicity against Stx1-sensitive cells. These results suggest that transgenic plants expressing SC-KDEL will provide a versatile means of SIgA production.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Almogren A, Senior BW, Kerr MA (2007) A comparison of the binding of secretory component to immunoglobulin A (IgA) in human colostral S-IgA1 and S-IgA2. Immunology 120:273–280. https://doi.org/10.1111/j.1365-2567.2006.02498.x
Brandtzaeg P (2013) Secretory IgA: designed for anti-microbial defense. Front Immunol 4:222. https://doi.org/10.3389/fimmu.2013.00222
Clough SJ, Bent AF (1998) Floral dip: a simplified method for Agrobacterium-mediated transformation of Arabidopsis thaliana. Plant J 16:735–743. https://doi.org/10.1046/j.1365-313x.1998.00343.x
Corthésy B (2013) Multi-faceted functions of secretory IgA at mucosal surfaces. Front Immunol 4:185. https://doi.org/10.3389/fimmu.2013.00185
Crottet P, Corthésy B (1998) Secretory component delays the conversion of secretory IgA into antigen-binding competent F(ab’)2: a possible implication for mucosal defense. J Immunol 161:5445–5453
Crottet P, Cottet S, Corthésy B (1999) Expression, purification and biochemical characterization of recombinant murine secretory component: a novel tool in mucosal immunology. Biochem J 341(Pt 2):299–306. https://doi.org/10.1042/bj3410299
da Cunha NB, Vianna GR, da Almeida Lima T, Rech E (2014) Molecular farming of human cytokines and blood products from plants: Challenges in biosynthesis and detection of plant-produced recombinant proteins. Biotechnol J 9:39–50. https://doi.org/10.1002/biot.201300062
Daniell H, Streatfield SJ, Wycoff K (2001) Medical molecular farming: Production of antibodies, biopharmaceuticals and edible vaccines in plants. Trends Plant Sci 6:219–226. https://doi.org/10.1016/S1360-1385(01)01922-7
De Meyer T, Depicker A (2014) Trafficking of endoplasmic reticulum-retained recombinant proteins is unpredictable in Arabidopsis thaliana. Front Plant Sci 5:473. https://doi.org/10.3389/fpls.2014.00473
Desai PN, Shrivastava N, Padh H (2010) Production of heterologous proteins in plants: Strategies for optimal expression. Biotechnol Adv 28:427–435. https://doi.org/10.1016/j.biotechadv.2010.01.005
Fasching CE, Grossman T, Corthesy B, Plaut AG, Weiser JN, Janoff EN (2007) Impact of the Molecular Form of Immunoglobulin A on Functional Activity in Defense against Streptococcus pneumoniae. Infect Immun 75:1801–1810. https://doi.org/10.1128/IAI.01758-06
Hirai T, Kurokawa N, Duhita N, Hiwasa-Tanase K, Kato K, Kato K, Ezura H (2011) The HSP terminator of Arabidopsis thaliana induces a high level of miraculin accumulation in transgenic tomatoes. J Agric Food Chem 59:9942–9949. https://doi.org/10.1021/jf202501e
Huang J, Guerrero A, Parker E, Strum JS, Smilowitz JT, German JB, Lebrilla CB (2015) Site-specific glycosylation of secretory immunoglobulin a from human colostrum. J Proteome Res 14:1335–1349. https://doi.org/10.1021/pr500826q
Imai Y, Nagai R, Ono Y, Ishikawa T, Nakagami H, Tanikawa T, Kurohane K (2004) Production of secretory immunoglobulin a against Shiga toxin-binding subunits in mice by mucosal immunization. Infect Immun 72:889–895. https://doi.org/10.1128/IAI.72.2.889-895.2004
Imai Y, Ishikawa T, Tanikawa T, Nakagami H, Maekawa T, Kurohane K (2005) Production of IgA monoclonal antibody against Shiga toxin binding subunits employing nasal-associated lymphoid tissue. J Immunol Methods 302:125–135. https://doi.org/10.1016/j.jim.2005.05.007
Ito Y, Eiguchi M, Kurata N (2001) KNOX homeobox genes are sufficient in maintaining cultured cells in an undifferentiated state in rice. Genesis 30:231–238. https://doi.org/10.1002/gene.1069
Johansen FE, Braathen R, Brandtzaeg P (2000) Role of J chain in secretory immunoglobulin formation. Scand J Immunol 52:240–248. https://doi.org/10.1046/j.1365-3083.2000.00790.x
Jones RM, Schweikart F, Frutiger S, Jaton JC, Hughes GJ (1998) Thiol-disulfide redox buffers maintain a structure of immunoglobulin A that is essential for optimal in vitro binding to secretory component. Biochim Biophys Acta Protein Struct Mol Enzymol 1429:265–274. https://doi.org/10.1016/S0167-4838(98)00239-8
Juarez P, Huet-Trujillo E, Sarrion-Perdigones A, Falconi EE, Granell A, Orzaez D (2013) Combinatorial analysis of secretory immunoglobulin A (sIgA) expression in plants. Int J Mol Sci 14:6205–6222. https://doi.org/10.3390/ijms14036205
Juarez P, Virdi V, Depicker A, Orzaez D (2016) Biomanufacturing of protective antibodies and other therapeutics in edible plant tissues for oral applications. Plant Biotechnol J 14:1791–1799. https://doi.org/10.1111/pbi.12541
Lindh E (1975) Increased resistance of immunoglobulin A dimers to proteolytic degradation after binding of secretory component. J Immunol 114:284–286
Longet S, Miled S, Lötscher M, Miescher SM, Zuercher AW, Corthésy B (2013) Human plasma-derived polymeric IgA and IgM antibodies associate with secretory component to yield biologically active secretory-like antibodies. J Biol Chem 288:4085–4094. https://doi.org/10.1074/jbc.M112.410811
Mantis NJ, Rol N, Corthésy B (2011) Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol 4:603–611. https://doi.org/10.1038/mi.2011.41
Mathias A, Corthésy B (2011a) N-glycans on secretory component: mediators of the interaction between secretory IgA and gram-positive commensals sustaining intestinal homeostasis. Gut Microbes 2:287–293. https://doi.org/10.4161/gmic.2.5.18269
Mathias A, Corthésy B (2011b) Recognition of gram-positive intestinal bacteria by hybridoma- and colostrum-derived secretory immunoglobulin A is mediated by carbohydrates. J Biol Chem 286:17239–17247. https://doi.org/10.1074/jbc.M110.209015
Miyashita S, Matsuura Y, Miyamoto D, Suzuki Y, Imai Y (1999) Development of recombinant B subunit of Shiga-like toxin 1 as a probe to detect carbohydrate ligands in immunochemical and flowcytometric application. Glycoconj J 16:697–705. https://doi.org/10.1023/A:1007107425891
Moldt B, Saye-Francisco K, Schultz N, Burton DR, Hessell AJ (2014) Simplifying the synthesis of SIgA: combination of dIgA and rhSC using affinity chromatography. Methods 65:127–132. https://doi.org/10.1016/j.ymeth.2013.06.022
Nagaya S, Kawamura K, Shinmyo A, Kato K (2010) The HSP terminator of Arabidopsis thaliana increases gene expression in plant cells. Plant Cell Physiol 51:328–332. https://doi.org/10.1093/pcp/pcp188
Nakanishi K, Narimatsu S, Ichikawa S, Tobisawa Y, Kurohane K, Niwa Y, Kobayashi H, Imai Y (2013) Production of Hybrid-IgG/IgA plantibodies with neutralizing activity against Shiga toxin 1. PLoS One 8:e80712. https://doi.org/10.1371/journal.pone.0080712
Nakanishi K, Morikane S, Ichikawa S, Kurohane K, Niwa Y, Akimoto Y, Matsubara S, Kawakami H, Kobayashi H, Imai Y (2017) Protection of human colon cells from Shiga toxin by plant-based recombinant secretory IgA. Sci Rep 7:45843. https://doi.org/10.1038/srep45843
Niwa Y, Goto S, Nakano T, Sakaiya M, Hirano T, Tsukaya H, Komeda Y, Kobayashi H (2006) Arabidopsis mutants by activation tagging in which photosynthesis genes are expressed in dedifferentiated calli. Plant Cell Physiol 47:319–331. https://doi.org/10.1093/pcp/pci242
Parr EL, Bozzola JJ, Parr MB (1995) Purification and measurement of secretory IgA in mouse milk. J Immunol Methods 180:147–157. https://doi.org/10.1016/0022-1759(94)00310-S
Phalipon A, Cardona A, Kraehenbuhl JP, Edelman L, Sansonetti PJ, Corthésy B (2002) Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo. Immunity 17:107–115. https://doi.org/10.1016/S1074-7613(02)00341-2
Reinhart D, Kunert R (2014) Upstream and downstream processing of recombinant IgA. Biotechnol Lett 37:241–251. https://doi.org/10.1007/s10529-014-1686-z
Schouten A, Roosien J, van Engelen FA, de Jong GA, Borst-Vrenssen AW, Zilverentant JF, Bosch D, Stiekema WJ, Gommers FJ, Schots A, Bakker J (1996) The C-terminal KDEL sequence increases the expression level of a single-chain antibody designed to be targeted to both the cytosol and the secretory pathway in transgenic tobacco. Plant Mol Biol 30:781–793. https://doi.org/10.1007/BF00019011
Segawa K, Kurata S, Yanagihashi Y, Brummelkamp TR, Matsuda F, Nagata S (2014) Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344:1164–1168. https://doi.org/10.1126/science.1252809
Shoji K, Takahashi T, Kurohane K, Iwata K, Matsuoka T, Tsuruta S, Sugino T, Miyake M, Suzuki T, Imai Y (2015) Recombinant immunoglobulin A specific for influenza A virus hemagglutinin: production, functional analysis, and formation of secretory immunoglobulin A. Viral Immunol 28:170–178. https://doi.org/10.1089/vim.2014.0098
Streatfield SJ, Kushnir N, Yusibov V (2015) Plant-produced candidate countermeasures against emerging and reemerging infections and bioterror agents. Plant Biotechnol J 13:1136–1159. https://doi.org/10.1111/pbi.12475
Sugio T, Satoh J, Matsuura H, Shinmyo A, Kato K (2008) The 5′-untranslated region of the Oryza sativa alcohol dehydrogenase gene functions as a translational enhancer in monocotyledonous plant cells. J Biosci Bioeng 105:300–302. https://doi.org/10.1263/jbb.105.300
Tanikawa T, Ishikawa T, Maekawa T, Kuronane K, Imai Y (2008) Characterization of monoclonal immunoglobulin A and G against Shiga toxin binding subunits produced by intranasal immunization. Scand J Immunol 68:414–422. https://doi.org/10.1111/j.1365-3083.2008.02153.x
Tesh VL (2010) Induction of apoptosis by Shiga toxins. Future Microbiol 5:431–453. https://doi.org/10.2217/fmb.10.4
Tobisawa Y, Maruyama T, Tanikawa T, Nakanishi K, Kurohane K, Imai Y (2011) Establishment of recombinant hybrid-IgG/IgA immunoglobulin specific for Shiga toxin. Scand J Immunol 74:574–584. https://doi.org/10.1111/j.1365-3083.2011.02617.x
Twyman RM, Schillberg S, Fischer R (2013) Optimizing the yield of recombinant pharmaceutical proteins in plants. Curr Pharm Des 19:5486–5494. https://doi.org/10.2174/1381612811319310004
Virdi V, Juarez P, Boudolf V, Depicker A (2016) Recombinant IgA production for mucosal passive immunization, advancing beyond the hurdles. Cell Mol Life Sci 73:535–545. https://doi.org/10.1007/s00018-015-2074-0
Woof JM, Kerr MA (2006) The function of immunoglobulin A in immunity. J Pathol 208:270–282. https://doi.org/10.1002/path.1877
Yamasaki S, Sanada Y, Imase R, Matsuura H, Ueno D, Demura T, Kato K (2018) Arabidopsis thaliana cold-regulated 47 gene 5′-untranslated region enables stable high-level expression of transgenes. J Biosci Bioeng 125:124–130. https://doi.org/10.1016/j.jbiosc.2017.08.007
Acknowledgements
This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers JP15H04660 and JP25670063 to YI; JP25·10915 to KN as well as by a research grant from the University of Shizuoka. We thank Mr. N.J. Halewood for language editing services.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declared that they have no conflict of interest.
Additional information
Communicated by Hiroshi Ezura.
Rights and permissions
About this article
Cite this article
Nakanishi, K., Morikane, S., Hosokawa, N. et al. Plant-derived secretory component forms secretory IgA with shiga toxin 1-specific dimeric IgA produced by mouse cells and whole plants. Plant Cell Rep 38, 161–172 (2019). https://doi.org/10.1007/s00299-018-2358-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00299-018-2358-6