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The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection

RIG-I (Retinoic Acid Inducible Gene-I) is a cytosolic innate immune receptor that detects atypical features in viral RNAs as foreign to initiate a Type I interferon signaling response. RIG-I is present in an autoinhibited state in the cytoplasm and activated by blunt-ended double-stranded (ds)RNAs c...

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Detalles Bibliográficos
Autores principales: Ramanathan, Anand, Devarkar, Swapnil C., Jiang, Fuguo, Miller, Matthew T., Khan, Abdul G., Marcotrigiano, Joseph, Patel, Smita S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
Materias:
RNA
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737149/
https://www.ncbi.nlm.nih.gov/pubmed/26612866
http://dx.doi.org/10.1093/nar/gkv1299
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author Ramanathan, Anand
Devarkar, Swapnil C.
Jiang, Fuguo
Miller, Matthew T.
Khan, Abdul G.
Marcotrigiano, Joseph
Patel, Smita S.
author_facet Ramanathan, Anand
Devarkar, Swapnil C.
Jiang, Fuguo
Miller, Matthew T.
Khan, Abdul G.
Marcotrigiano, Joseph
Patel, Smita S.
author_sort Ramanathan, Anand
collection PubMed
description RIG-I (Retinoic Acid Inducible Gene-I) is a cytosolic innate immune receptor that detects atypical features in viral RNAs as foreign to initiate a Type I interferon signaling response. RIG-I is present in an autoinhibited state in the cytoplasm and activated by blunt-ended double-stranded (ds)RNAs carrying a 5′ triphosphate (ppp) moiety. These features found in many pathogenic RNAs are absent in cellular RNAs due to post-transcriptional modifications of RNA ends. Although RIG-I is structurally well characterized, the mechanistic basis for RIG-I's remarkable ability to discriminate between cellular and pathogenic RNAs is not completely understood. We show that RIG-I's selectivity for blunt-ended 5′-ppp dsRNAs is ≈3000 times higher than non-blunt ended dsRNAs commonly found in cellular RNAs. Discrimination occurs at multiple stages and signaling RNAs have high affinity and ATPase turnover rate and thus a high k(atpase)/K(d). We show that RIG-I uses its autoinhibitory CARD2-Hel2i (second CARD-helicase insertion domain) interface as a barrier to select against non-blunt ended dsRNAs. Accordingly, deletion of CARDs or point mutations in the CARD2-Hel2i interface decreases the selectivity from ≈3000 to 150 and 750, respectively. We propose that the CARD2-Hel2i interface is a ‘gate’ that prevents cellular RNAs from generating productive complexes that can signal.
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spelling pubmed-47371492016-02-03 The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection Ramanathan, Anand Devarkar, Swapnil C. Jiang, Fuguo Miller, Matthew T. Khan, Abdul G. Marcotrigiano, Joseph Patel, Smita S. Nucleic Acids Res RNA RIG-I (Retinoic Acid Inducible Gene-I) is a cytosolic innate immune receptor that detects atypical features in viral RNAs as foreign to initiate a Type I interferon signaling response. RIG-I is present in an autoinhibited state in the cytoplasm and activated by blunt-ended double-stranded (ds)RNAs carrying a 5′ triphosphate (ppp) moiety. These features found in many pathogenic RNAs are absent in cellular RNAs due to post-transcriptional modifications of RNA ends. Although RIG-I is structurally well characterized, the mechanistic basis for RIG-I's remarkable ability to discriminate between cellular and pathogenic RNAs is not completely understood. We show that RIG-I's selectivity for blunt-ended 5′-ppp dsRNAs is ≈3000 times higher than non-blunt ended dsRNAs commonly found in cellular RNAs. Discrimination occurs at multiple stages and signaling RNAs have high affinity and ATPase turnover rate and thus a high k(atpase)/K(d). We show that RIG-I uses its autoinhibitory CARD2-Hel2i (second CARD-helicase insertion domain) interface as a barrier to select against non-blunt ended dsRNAs. Accordingly, deletion of CARDs or point mutations in the CARD2-Hel2i interface decreases the selectivity from ≈3000 to 150 and 750, respectively. We propose that the CARD2-Hel2i interface is a ‘gate’ that prevents cellular RNAs from generating productive complexes that can signal. Oxford University Press 2016-01-29 2015-11-26 /pmc/articles/PMC4737149/ /pubmed/26612866 http://dx.doi.org/10.1093/nar/gkv1299 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. 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 reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle RNA
Ramanathan, Anand
Devarkar, Swapnil C.
Jiang, Fuguo
Miller, Matthew T.
Khan, Abdul G.
Marcotrigiano, Joseph
Patel, Smita S.
The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection
title The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection
title_full The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection
title_fullStr The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection
title_full_unstemmed The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection
title_short The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection
title_sort autoinhibitory card2-hel2i interface of rig-i governs rna selection
topic RNA
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737149/
https://www.ncbi.nlm.nih.gov/pubmed/26612866
http://dx.doi.org/10.1093/nar/gkv1299
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