Dcp2 Decapping Protein Modulates mRNA Stability of the Critical Interferon Regulatory Factor (IRF) IRF-7

Abstract

bThe mammalian Dcp2 mRNA-decapping protein functions primarily on a subset of mRNAs in a transcript-specific manner. Here we show that Dcp2 is an important modulator of genes involved in the type I interferon (IFN) response, which is the initial line of antiviral innate immune response elicited by a viral challenge. Mouse embryonic fibroblast cells with reduced Dcp2 levels (Dcp2 ␤/␤ ) contained significantly elevated levels of mRNAs encoding proteins involved in the type I IFN response. In particular, analysis of a key type I IFN transcription factor, IFN regulatory factor 7 (IRF-7), revealed an increase in both IRF-7 mRNA and protein in Dcp2 ␤/␤ cells. Importantly, the increase in IRF-7 mRNA within the background of reduced Dcp2 levels was attributed to a stabilization of the IRF-7 mRNA, suggesting that Dcp2 normally modulates IRF-7 mRNA stability. Moreover, Dcp2 expression was also induced upon viral infection, consistent with a role in attenuating the antiviral response by promoting IRF-7 mRNA degradation. The induction of Dcp2 levels following a viral challenge and the specificity of Dcp2 in targeting the decay of IRF-7 mRNA suggest that Dcp2 may negatively contribute to the innate immune response in a negative feedback mechanism to restore normal homeostasis following viral infection.

A genome-wide RNAi screen reveals that mRNA decapping restricts bunyaviral replication by limiting the pools of Dcp2-accessible targets for cap-snatching

“…These findings suggest that Dcp2 restricts the RNA substrates available for RVFV-mediated cap-snatching and does not globally affect the cap status of mRNAs within the cell. This is consistent with the finding that Dcp2 does not globally regulate mRNA turnover but impacts the stability of only small subsets of mRNAs from yeast to humans (Li et al 2008b(Li et al , 2012Yoon et al 2010). Furthermore, depletion of the P-body-resident 59-to-39 exonuclease Xrn1 does not impact viral infection levels, N transcript levels, or digestion assay results, suggesting that viral mRNAs Mean 6 SD for three or more independent experiments; no time points were significantly different.…”

Multiple Nudix family proteins possess mRNA decapping activity

“…Our recent demonstration that Nudt16 is also a mammalian decapping protein and that both Dcp2 and Nudt16 each preferentially functions on a subset of mRNAs and pathways (Song et al 2010;Li et al 2011Li et al , 2012 raised the possibility that additional decapping enzymes are functional in mammalian cells. To evaluate whether proteins in addition to the two known Nudix decapping proteins possess decapping activity, we tested all known mouse Nudix proteins in vitro and identified six additional potential mammalian decapping enzymes-Nudt2, Nudt3, Nudt12, Nudt15, Nudt17, and Nudt19 (Fig.…”

Two-headed tetraphosphate cap analogs are inhibitors of the Dcp1/2 RNA decapping complex

“…The structures of identified inhibitors may also serve as a starting point for the design of molecular probes to test Dcp2 binding or activity in high throughput format. Interestingly, recent studies have implicated Dcp2 in some diseases related to SMN assembly (Shukla and Parker 2014) and interferon response (Li et al 2012). These findings suggest that small molecules targeting Dcp2 may also be interesting from a pharmacological point of view, and biophysical and biochemical insight into Dcp2 structure and function gained from studies using the tightly bound cap analogs described here may be important for the development of therapeutically relevant Dcp2 inhibitors.…”

“…Identification of such compounds would not only be useful in structural and biochemical studies on Dcp2 activity and cap binding, but would also potentially allow identification of inhibitor binding sites and pave the way for the development of novel Dcp2 inhibitors. Recent studies link Dcp2 activity to spinal muscular atrophy (Shukla and Parker 2014) and the interferon response (Li et al 2012) in mammalian cells, suggesting that development of selective Dcp2 inhibitors may be medically useful.…”