DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity

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.

DUSP11 and triphosphate RNA balance during virus infection

“…Studies reveal the importance of proper control of endogenous cellular triphosphate RNA levels, including appropriate subcellular localization and protein shielding of the 5′-end of host RNAP III transcripts to reduce exposure to RIG-I [ 7 – 10 ]. More recently, the cellular triphosphatase dual-specificity phosphatase (DUSP) 11 is emerging as an important player in maintaining triphosphate RNA balance [ 11 – 17 ]. Either increased or decreased levels of DUSP11 can decrease or increase, respectively, the propensity of a cell to undergo the antiviral response ( Fig 1 ).…”

“…Transcriptome-wide analyses reveal that a subset of RNAP III transcripts (vault, RNA component of mitochondrial RNA processing (RMRP), Alu short interspersed nuclear element (SINE), and Y RNAs) are not only more likely to be triphosphorylated but are also more abundant in cells lacking DUSP11 [ 11 ]. Exposure of DUSP11-deficient cells to exogenous in vitro synthesized 5′-PPP RNA results in an enhanced increase in the expression of interferon-associated genes [ 15 , 17 ]. This phenotype requires RIG-I, a PRR that triggers the interferon response upon detection of structured 5′-PPP RNAs [ 17 ].…”

“…Exposure of DUSP11-deficient cells to exogenous in vitro synthesized 5′-PPP RNA results in an enhanced increase in the expression of interferon-associated genes [ 15 , 17 ]. This phenotype requires RIG-I, a PRR that triggers the interferon response upon detection of structured 5′-PPP RNAs [ 17 ]. Consistent with these aberrant RNAs having biological impact, DUSP11-deficient mice display a signature of enhanced interferon signaling and show greater sensitivity to exogenous 5'-PPP RNA [ 17 ].…”

“…This phenotype requires RIG-I, a PRR that triggers the interferon response upon detection of structured 5′-PPP RNAs [ 17 ]. Consistent with these aberrant RNAs having biological impact, DUSP11-deficient mice display a signature of enhanced interferon signaling and show greater sensitivity to exogenous 5'-PPP RNA [ 17 ].…”

“…The EV 7SL RNA cargo is subsequently detected by RIG-I in recipient tumor cells [ 8 , 9 ]. Interestingly, DUSP11 also participates in control of the inflammatory potential of EVs derived from tumor–stromal cell coculture [ 17 ]. Thus, triphosphate balance is maintained by multiple mechanisms including shielding of immunostimulatory RNAs by RBPs and dephosphorylating 5′-PPP RNAs by phosphatases such as DUSP11 ( Fig 2 ).…”