Abstract
Ricin, a highly lethal plant-derived toxin, is a potential biological threat agent due to its high availability, ease of production and the lack of approved medical countermeasures for post-exposure treatment. To date, no specific ricin receptors were identified. Here we show for the first time, that the low density lipoprotein receptor-related protein-1 (LRP1) is a major target molecule for binding of ricin. Pretreating HEK293 acetylcholinesterase-producer cells with either anti-LRP1 antibodies or with Receptor-Associated Protein (a natural LRP1 antagonist), or using siRNA to knock-down LRP1 expression resulted in a marked reduction in their sensitivity towards ricin. Binding assays further demonstrated that ricin bound exclusively to the cluster II binding domain of LRP1, via the ricin B subunit. Ricin binding to the cluster II binding domain of LRP1 was significantly reduced by an anti-ricin monoclonal antibody, which confers high-level protection to ricin pulmonary-exposed mice. Finally, we tested the contribution of LRP1 receptor to ricin intoxication of lung cells derived from mice. Treating these cells with anti-LRP1 antibody prior to ricin exposure, prevented their intoxication. Taken together, our findings clearly demonstrate that the LRP1 receptor plays an important role in ricin-induced pulmonary intoxications.
Highlights
Ricin, a highly lethal plant-derived toxin, is a potential biological threat agent due to its high availability, ease of production and the lack of approved medical countermeasures for post-exposure treatment
To examine whether ricin binds in a differential manner to cell-surface proteins, murine lung cell membrane proteins were resolved by SDS-PAGE and transferred to absorbent membranes which were incubated with purified preparations of either ricin or ricin-related Ricinus communis agglutinin (RCA)
Labeling with polyclonal anti-ricin antibody, which interacts with both ricin and RCA, revealed that while RCA seems to bind in an indiscriminate manner to a wide range of lung cell membrane proteins, purified ricin was found to bind to a limited number of discrete protein bands (Fig. 1)
Summary
A highly lethal plant-derived toxin, is a potential biological threat agent due to its high availability, ease of production and the lack of approved medical countermeasures for post-exposure treatment. Previous studies at our laboratory showed that following pulmonary exposure of mice to ricin, the toxin displays differential patterns of binding with various lung-cell populations and that ricin-induced depurination levels in these cells differed markedly[7,8] These findings, which suggest that ricin enters different cells in a selective manner led us to investigate whether the ricin molecule binds to specific cell-surface receptors. We show that prevention of ricin binding to this receptor is sufficient to protect cultured cells as well as primary lung cells from intoxication These findings demonstrate for the first time that the transmembrane receptor LRP1 plays a central role in ricin poisoning and open new vistas for the development of novel therapeutic agents for dealing with ricin-induced intoxications
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