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Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathw...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591055/ https://www.ncbi.nlm.nih.gov/pubmed/33057424 http://dx.doi.org/10.1371/journal.ppat.1008999 |
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author | Webb, L. G. Veloz, J. Pintado-Silva, J. Zhu, T. Rangel, M. V. Mutetwa, T. Zhang, L. Bernal-Rubio, D. Figueroa, D. Carrau, L. Fenutria, R. Potla, U. Reid, St. P. Yount, J. S. Stapleford, K. A. Aguirre, S. Fernandez-Sesma, A. |
author_facet | Webb, L. G. Veloz, J. Pintado-Silva, J. Zhu, T. Rangel, M. V. Mutetwa, T. Zhang, L. Bernal-Rubio, D. Figueroa, D. Carrau, L. Fenutria, R. Potla, U. Reid, St. P. Yount, J. S. Stapleford, K. A. Aguirre, S. Fernandez-Sesma, A. |
author_sort | Webb, L. G. |
collection | PubMed |
description | Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathways in the host recognition of CHIKV; however, less is known regarding antagonism of CHIKV by cytosolic DNA sensing pathways like that of cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). With the use of cGAS or STING null cells we demonstrate that the pathway restricts CHIKV replication in fibroblasts and immune cells. We show that DNA accumulates in the cytoplasm of infected cells and that CHIKV blocks DNA dependent IFN-β transcription. This antagonism of DNA sensing is via an early autophagy-mediated degradation of cGAS and expression of the CHIKV capsid protein is sufficient to induce cGAS degradation. Furthermore, we identify an interaction of CHIKV nsP1 with STING and map the interaction to 23 residues in the cytosolic loop of the adaptor protein. This interaction stabilizes the viral protein and increases the level of palmitoylated nsP1 in cells. Together, this work supports previous publications highlighting the relevance of the cGAS-STING pathway in the early detection of (+)ssRNA viruses and provides direct evidence that CHIKV interacts with and antagonizes cGAS-STING signaling. |
format | Online Article Text |
id | pubmed-7591055 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-75910552020-10-30 Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS Webb, L. G. Veloz, J. Pintado-Silva, J. Zhu, T. Rangel, M. V. Mutetwa, T. Zhang, L. Bernal-Rubio, D. Figueroa, D. Carrau, L. Fenutria, R. Potla, U. Reid, St. P. Yount, J. S. Stapleford, K. A. Aguirre, S. Fernandez-Sesma, A. PLoS Pathog Research Article Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathways in the host recognition of CHIKV; however, less is known regarding antagonism of CHIKV by cytosolic DNA sensing pathways like that of cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). With the use of cGAS or STING null cells we demonstrate that the pathway restricts CHIKV replication in fibroblasts and immune cells. We show that DNA accumulates in the cytoplasm of infected cells and that CHIKV blocks DNA dependent IFN-β transcription. This antagonism of DNA sensing is via an early autophagy-mediated degradation of cGAS and expression of the CHIKV capsid protein is sufficient to induce cGAS degradation. Furthermore, we identify an interaction of CHIKV nsP1 with STING and map the interaction to 23 residues in the cytosolic loop of the adaptor protein. This interaction stabilizes the viral protein and increases the level of palmitoylated nsP1 in cells. Together, this work supports previous publications highlighting the relevance of the cGAS-STING pathway in the early detection of (+)ssRNA viruses and provides direct evidence that CHIKV interacts with and antagonizes cGAS-STING signaling. Public Library of Science 2020-10-15 /pmc/articles/PMC7591055/ /pubmed/33057424 http://dx.doi.org/10.1371/journal.ppat.1008999 Text en © 2020 Webb et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Webb, L. G. Veloz, J. Pintado-Silva, J. Zhu, T. Rangel, M. V. Mutetwa, T. Zhang, L. Bernal-Rubio, D. Figueroa, D. Carrau, L. Fenutria, R. Potla, U. Reid, St. P. Yount, J. S. Stapleford, K. A. Aguirre, S. Fernandez-Sesma, A. Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS |
title | Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS |
title_full | Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS |
title_fullStr | Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS |
title_full_unstemmed | Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS |
title_short | Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS |
title_sort | chikungunya virus antagonizes cgas-sting mediated type-i interferon responses by degrading cgas |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591055/ https://www.ncbi.nlm.nih.gov/pubmed/33057424 http://dx.doi.org/10.1371/journal.ppat.1008999 |
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