Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I
The cytoplasmic immune sensor RIG-I detects viral RNA and initiates an antiviral immune response upon activation. It has become a potential target for vaccination and immunotherapies. To develop the smallest but potent immunomodulatory RNA (immRNAs) species, we performed structure-guided RNA design...
| Main Authors: | , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Online Access: | https://hdl.handle.net/10356/149909 |
| _version_ | 1811676236588515328 |
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| author | Yong, Hui Yee Zheng, Jie Ho, Victor Chin Yong Nguyen, Mai Trinh Fink, Katja Griffin, Patrick R. Luo, Dahai |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Yong, Hui Yee Zheng, Jie Ho, Victor Chin Yong Nguyen, Mai Trinh Fink, Katja Griffin, Patrick R. Luo, Dahai |
| author_sort | Yong, Hui Yee |
| collection | NTU |
| description | The cytoplasmic immune sensor RIG-I detects viral RNA and initiates an antiviral immune response upon activation. It has become a potential target for vaccination and immunotherapies. To develop the smallest but potent immunomodulatory RNA (immRNAs) species, we performed structure-guided RNA design and used biochemical, structural, and cell-based methods to select and characterize the immRNAs. We demonstrated that inserting guanosine at position 9 to the 10mer RNA hairpin (3p10LG9) activates RIG-I more robustly than the parental RNA. 3p10LG9 interacts strongly with the RIG-I helicase-CTD RNA sensing module and disrupts the auto-inhibitory interaction between the HEL2i and CARDs domains. We further showed that 3p10LA9 has a stronger cellular activity than 3p10LG9. Collectively, purine insertion at position 9 of the immRNA species triggered more robust activation of RIG-1. |
| first_indexed | 2024-10-01T02:18:16Z |
| format | Journal Article |
| id | ntu-10356/149909 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:18:16Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1499092023-02-28T17:09:30Z Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I Yong, Hui Yee Zheng, Jie Ho, Victor Chin Yong Nguyen, Mai Trinh Fink, Katja Griffin, Patrick R. Luo, Dahai Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences Singapore Immunology Network, A*STAR NTU Institute of Structural Biology Science::Biological sciences Immunomodulatory RNAs The cytoplasmic immune sensor RIG-I detects viral RNA and initiates an antiviral immune response upon activation. It has become a potential target for vaccination and immunotherapies. To develop the smallest but potent immunomodulatory RNA (immRNAs) species, we performed structure-guided RNA design and used biochemical, structural, and cell-based methods to select and characterize the immRNAs. We demonstrated that inserting guanosine at position 9 to the 10mer RNA hairpin (3p10LG9) activates RIG-I more robustly than the parental RNA. 3p10LG9 interacts strongly with the RIG-I helicase-CTD RNA sensing module and disrupts the auto-inhibitory interaction between the HEL2i and CARDs domains. We further showed that 3p10LA9 has a stronger cellular activity than 3p10LG9. Collectively, purine insertion at position 9 of the immRNA species triggered more robust activation of RIG-1. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University National Medical Research Council (NMRC) Accepted version This work was supported by a start-up grant from LeeKong Chian School of Medicine, Nanyang Technolog-ical University and the National Medical ResearchCouncil grant OFIRG17nov084 to DL lab. HDX-MSwork was supported by NIH grants NIGMS P50GM103368 (PRG). This work was also supported byA*STAR core funding to SIgN. HCYV was the recipi-ent of a fellowship from A*GA under the SIgN-NTUPhD program. 2021-05-25T02:26:45Z 2021-05-25T02:26:45Z 2019 Journal Article Yong, H. Y., Zheng, J., Ho, V. C. Y., Nguyen, M. T., Fink, K., Griffin, P. R. & Luo, D. (2019). Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I. FEBS Letters, 593(21), 3003-3014. https://dx.doi.org/10.1002/1873-3468.13564 0014-5793 0000-0001-7637-7275 https://hdl.handle.net/10356/149909 10.1002/1873-3468.13564 31369683 2-s2.0-85070797783 21 593 3003 3014 en OFIRG17nov084 NIGMS P50GM103368 (PRG) FEBS Letters © 2019 Federation of European Biochemical Societies. All rights reserved. This paper was published by Wiley in FEBS Letters and is made available with permission of Federation of European Biochemical Societies. application/pdf |
| spellingShingle | Science::Biological sciences Immunomodulatory RNAs Yong, Hui Yee Zheng, Jie Ho, Victor Chin Yong Nguyen, Mai Trinh Fink, Katja Griffin, Patrick R. Luo, Dahai Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I |
| title | Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I |
| title_full | Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I |
| title_fullStr | Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I |
| title_full_unstemmed | Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I |
| title_short | Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I |
| title_sort | structure guided design of immunomodulatory rnas specifically targeting the cytoplasmic viral rna sensor rig i |
| topic | Science::Biological sciences Immunomodulatory RNAs |
| url | https://hdl.handle.net/10356/149909 |
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