Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response

Sneha Rath; Eliza Prangley; Jesse Donovan; Kaitlin Demarest; Yigal Meir; Ned Wingreen; Alexei Korennykh

Our work suggests that in mammalian cells decay of abundant mRNAs can be efficiently coupled with a kinetically matched transcriptional response to steer translation toward stress proteins. Since the discovery of translational inhibition by 2-5AMD in 1977 (Hovanessian et al., 1977) , various hypotheses have been proposed to explain how this mechanism contributes to the IFN response and how mammals may use 2-5AMD to cope with stress conditions associated with dsRNA. The hypothesized functions ranged from antiviral defense due to viral RNA decay (Cooper et al., 2014a; Han et al., 2004; Nilsen and Baglioni, 1979) to IFN amplification by cleaved self-RNAs (Malathi et al., 2007) or destruction of host RNAs as a mechanism to kill infected cells during the late pro-apoptotic stages of dsRNA sensing (Chakrabarti et al., 2011; Zhou et al., 1997) . The observations that 2-5AMD can begin early and precede the IFN response, and that IFNs The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/484675 doi: bioRxiv preprint investigation. Our model, based on analysis of 2-5AMD in human A549 cells, is summarized in Figure 7F . We show that the loss of protein synthesis can be explained by depletion of thousands of host mRNAs. The same mechanistic conclusion is made in a manuscript submitted back to back with our work (Burke et al., and Roy Parker [ref will