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Abstract
mRNA medicines can be used to express therapeutic proteins, but the production of such proteins in non-target cells has a risk of adverse effects. To accurately distinguish between therapeutic target and nontarget cells, it is desirable to utilize multiple proteins expressed in each cell as indicators. To achieve such multi-input translational regulation of mRNA medicines, in this study, we engineered Rhodothermus marinus (Rma) DnaB intein to develop “caged Rma DnaB intein” that enables conditional reconstitution of full-length translational regulator protein from split fragments. By combining the caged Rma DnaB intein, the split translational regulator protein, and target protein-binding domains, we succeeded in target protein-dependent translational repression of mRNA in human cells. In addition, the caged Rma intein showed orthogonality to the previously reported Nostoc punctiforme (Npu) DnaE-based caged intein. Finally, by combining these two orthogonal caged inteins, we developed an mRNA-based logic gate that regulates translation based on the expression of multiple intracellular proteins. This study provides important information to develop safer mRNA medicines.
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Details
1 Tokyo Medical and Dental University (TMDU), Department of Biofunction Research, Institute of Biomaterials and Bioengineering, Tokyo, Japan (GRID:grid.265073.5) (ISNI:0000 0001 1014 9130)
2 Tokyo Medical and Dental University (TMDU), Department of Biofunction Research, Institute of Biomaterials and Bioengineering, Tokyo, Japan (GRID:grid.265073.5) (ISNI:0000 0001 1014 9130); Osaka University, Center for Infectious Disease Education and Research (CiDER), Osaka, Japan (GRID:grid.136593.b) (ISNI:0000 0004 0373 3971)