DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity
- Joon H. Choi,
- James M. Burke1,
- Kayla H. Szymanik,
- Upasana Nepal,
- Anna Battenhouse,
- Justin T. Lau,
- Aaron Stark,
- Victor Lam2 and
- Christopher S. Sullivan
- Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, The University of Texas at Austin, Austin Texas 78712, USA
- Corresponding author: chris_sullivan{at}austin.utexas.edu
Abstract
Deciphering the mechanisms that regulate the sensitivity of pathogen recognition receptors is imperative to understanding infection and inflammation. Here we demonstrate that the RNA triphosphatase dual-specificity phosphatase 11 (DUSP11) acts on both host and virus-derived 5′-triphosphate RNAs rendering them less active in inducing a RIG-I-mediated immune response. Reducing DUSP11 levels alters host triphosphate RNA packaged in extracellular vesicles and induces enhanced RIG-I activation in cells exposed to extracellular vesicles. Virus infection of cells lacking DUSP11 results in a higher proportion of triphosphorylated viral transcripts and attenuated virus replication, which is rescued by reducing RIG-I expression. Consistent with the activity of DUSP11 in the cellular RIG-I response, mice lacking DUSP11 display lower viral loads, greater sensitivity to triphosphorylated RNA, and a signature of enhanced interferon activity in select tissues. Our results reveal the importance of controlling 5′-triphosphate RNA levels to prevent aberrant RIG-I signaling and demonstrate DUSP11 as a key effector of this mechanism.
Keywords
- DUSP11
- RIG-I signaling
- inflammation
- innate immunity
- noncoding RNA
- tumor–stromal interaction
- virus infection
Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.340604.120.
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Freely available online through the Genes & Development Open Access option.
- Received June 18, 2020.
- Accepted September 28, 2020.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.