Role of RNA phosphatase DUSP11 in noncoding RNA immunity
The mammalian innate immune system utilizes pattern-recognition receptors (PRRs) that monitor cells to detect pathogen-associated molecular patterns (PAMPs). Structured double-stranded RNAs containing a 5'-triphosphate moiety are hallmarks of virus infection and are thus well-studied PAMPs sensed by PRR RIG-I. All host RNA polymerase transcripts are also initially 5'-triphosphorylated but are immediately processed or post-transcriptionally modified with the exception of select RNA polymerase III (RNAP III) transcripts. Accumulating evidence suggests that RIG-I can also detect endogenous RNAP III transcripts and activate the antiviral response. This indicates the importance of proper control of cellular triphosphate RNA levels to prevent infection and inflammation. Previous work from our lab and others suggests RNA phosphatase DUSP11 as a modulator of 5'-triphosphate RNA. However, DUSP11's physiological role in the innate immune response and its regulation of pro-inflammatory RNAP III transcripts remained unknown. In the first study, we focus on understanding the function of DUSP11 in modulating the antiviral RIG-I response. Our work demonstrates that the catalytic phosphatase activity of DUSP11 renders both host and viral 5'-triphosphate RNAs less visible to RIG-I. We further observe that cells and mice absent of DUSP11 display greater sensitivity towards triphosphate RNAs and provide enhanced protection against virus infection. This study suggests DUSP11 control of triphosphate RNAs as an additional host mechanism to maintain a properly tuned immune response. Second, we demonstrate that RNAP III transcripts are controlled through a DUSP11-dependent decay pathway. Subcellular fractionation reveals that DUSP11's regulation of RNAP III transcripts can function in the nucleus. RNAP III transcripts from cells absent of DUSP11 display increased RNA half-life, indicating that DUSP11's phosphatase activity further renders these transcripts for decay. Taken together, we propose that DUSP11 functions as a critical factor in balancing cellular triphosphate RNA levels, which dictates the propensity of the cell to undergo the antiviral response. This work establishes DUSP11 as a key modulator of 5'-triphosphate RNAs that can alter RIG-I sensitivity and control the levels of pro-inflammatory RNAP III transcripts.