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The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation
Dengue virus (DENV) is one of the most prevalent mosquito-transmitted human viruses that causes significant morbidity and mortality worldwide. To persist in the cell and consequently cause disease, DENV is evolved with mechanisms to suppress the induction of type I interferons by antagonizing cGAS-S...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Biochemistry and Molecular Biology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011430/ https://www.ncbi.nlm.nih.gov/pubmed/36754281 http://dx.doi.org/10.1016/j.jbc.2023.102986 |
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author | Bhattacharya, Madhurima Bhowmik, Debipreeta Tian, Yuan He, Huan Zhu, Fanxiu Yin, Qian |
author_facet | Bhattacharya, Madhurima Bhowmik, Debipreeta Tian, Yuan He, Huan Zhu, Fanxiu Yin, Qian |
author_sort | Bhattacharya, Madhurima |
collection | PubMed |
description | Dengue virus (DENV) is one of the most prevalent mosquito-transmitted human viruses that causes significant morbidity and mortality worldwide. To persist in the cell and consequently cause disease, DENV is evolved with mechanisms to suppress the induction of type I interferons by antagonizing cGAS-STING signaling. Using recombinant proteins and in vitro cleavage assays, we have shown that the DENV protease NS2B3 is capable of cleaving cGAS in the N-terminal region without disrupting the C-terminal catalytic center. This generates two major cleavage products: cleavage product N-terminal (CP-N) and cleavage product C-terminal (CP-C). We observed reduction in DNA-binding affinity of CP-C as compared to full-length cGAS. Reduction in DNA-binding affinity is also correlated with the decrease in enzymatic activity of CP-C. CP-N, on the other hand, has almost comparable DNA-binding ability as that of the full-length cGAS. In fact, CP-N competitively inhibits cyclic GMP-AMP production by both full-length cGAS and CP-C. We hypothesize that high DNA-binding affinity of CP-N enables it to sequester the DNA from CP-C and noncleaved full-length cGAS and thus reduces the rate of enzyme activation and cyclic GMP-AMP synthesis. Furthermore, we found that NS2B3 physically interacts with full-length cGAS and CP-C, laying the basis for their shuttling to and eventual degradation in the autophagosome. Overall, our study highlights a multifaceted and effective strategy by which an RNA virus antagonizes cGAS-STING signaling which may be useful for the design of antivirals targeting viral proteases. |
format | Online Article Text |
id | pubmed-10011430 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-100114302023-03-15 The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation Bhattacharya, Madhurima Bhowmik, Debipreeta Tian, Yuan He, Huan Zhu, Fanxiu Yin, Qian J Biol Chem Research Article Collection: Virology Dengue virus (DENV) is one of the most prevalent mosquito-transmitted human viruses that causes significant morbidity and mortality worldwide. To persist in the cell and consequently cause disease, DENV is evolved with mechanisms to suppress the induction of type I interferons by antagonizing cGAS-STING signaling. Using recombinant proteins and in vitro cleavage assays, we have shown that the DENV protease NS2B3 is capable of cleaving cGAS in the N-terminal region without disrupting the C-terminal catalytic center. This generates two major cleavage products: cleavage product N-terminal (CP-N) and cleavage product C-terminal (CP-C). We observed reduction in DNA-binding affinity of CP-C as compared to full-length cGAS. Reduction in DNA-binding affinity is also correlated with the decrease in enzymatic activity of CP-C. CP-N, on the other hand, has almost comparable DNA-binding ability as that of the full-length cGAS. In fact, CP-N competitively inhibits cyclic GMP-AMP production by both full-length cGAS and CP-C. We hypothesize that high DNA-binding affinity of CP-N enables it to sequester the DNA from CP-C and noncleaved full-length cGAS and thus reduces the rate of enzyme activation and cyclic GMP-AMP synthesis. Furthermore, we found that NS2B3 physically interacts with full-length cGAS and CP-C, laying the basis for their shuttling to and eventual degradation in the autophagosome. Overall, our study highlights a multifaceted and effective strategy by which an RNA virus antagonizes cGAS-STING signaling which may be useful for the design of antivirals targeting viral proteases. American Society for Biochemistry and Molecular Biology 2023-02-07 /pmc/articles/PMC10011430/ /pubmed/36754281 http://dx.doi.org/10.1016/j.jbc.2023.102986 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Collection: Virology Bhattacharya, Madhurima Bhowmik, Debipreeta Tian, Yuan He, Huan Zhu, Fanxiu Yin, Qian The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation |
title | The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation |
title_full | The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation |
title_fullStr | The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation |
title_full_unstemmed | The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation |
title_short | The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation |
title_sort | dengue virus protease ns2b3 cleaves cyclic gmp-amp synthase to suppress cgas activation |
topic | Research Article Collection: Virology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011430/ https://www.ncbi.nlm.nih.gov/pubmed/36754281 http://dx.doi.org/10.1016/j.jbc.2023.102986 |
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