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Exogenous Peptides Delivered by Ricin Require Processing by Signal Peptidase for Transporter Associated with Antigen Processing-Independent MHC Class I-Restricted Presentation¹

Daniel C. Smith^*, Awen Gallimore, Emma Jones, Brenda Roberts^*, J. Michael Lord^*, Emma Deeks^*, Vincenzo Cerundolo and Lynne M. Roberts^2,*

^* Department of Biological Sciences, University of Warwick, Coventry, United Kingdom; and Molecular Immunology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom

In this study we demonstrate that a disarmed version of the cytotoxin ricin can deliver exogenous CD8⁺ T cell epitopes into the MHC class I-restricted pathway by a TAP-independent, signal peptidase-dependent pathway. Defined viral peptide epitopes genetically fused to the N terminus of an attenuated ricin A subunit (RTA) that was reassociated with its partner B subunit were able to reach the early secretory pathway of sensitive cells, including TAP-deficient cells. Successful processing and presentation by MHC class I proteins was not dependent on proteasome activity or on recycling of MHC class I proteins, but rather on a functional secretory pathway. Our results demonstrated a role for signal peptidase in the generation of peptide epitopes associated at the amino terminus of RTA. We showed, first, that potential signal peptide cleavage sites located toward the N terminus of RTA can be posttranslationally cleaved by signal peptidase and, second, that mutation of one of these sites led to a loss of peptide presentation. These results identify a novel MHC class I presentation pathway that exploits the ability of toxins to reach the lumen of the endoplasmic reticulum by retrograde transport, and suggest a role for endoplasmic reticulum signal peptidase in the processing and presentation of MHC class I peptides. Because TAP-negative cells can be sensitized for CTL killing following retrograde transport of toxin-linked peptides, application of these results has direct implications for the development of novel vaccination strategies.

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				K. L. Chamberlain, R. S. Marshall, N. A. Jolliffe, L. Frigerio, A. Ceriotti, J. M. Lord, and L. M. Roberts Ricin B Chain Targeted to the Endoplasmic Reticulum of Tobacco Protoplasts Is Degraded by a CDC48- and Vacuole-independent Mechanism J. Biol. Chem., November 28, 2008; 283(48): 33276 - 33286. [Abstract] [Full Text] [PDF]