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

In the presence of normal cap-dependent initiation and functional ribosomes, the loss of cell-wide protein synthesis (Fig. 1C, Fig. S1A -B) may arise from cleavage of a non-ribosomal RNA essential for global translation. Cleavage of a tRNA would satisfy this criterion, and tRNA cleavage has been previously demonstrated . However, even the most sensitive tRNAs were intact at the time of translational inhibition, suggesting that the only RNA substrates that could account for the translational inhibition are mRNAs. RNase L has been shown to cleave exogenous mRNAs, viral mRNAs and select host mRNAs with a preference for longer RNAs with many AU-rich elements due to the specificity of RNase L for UN^N sites (Al-Ahmadi et al., 2009; Le Roy et al., 2007; Nogimori et al., 2018; Rath et al., 2015) . To produce the uniform loss of global translation by mRNA decay, 2-5AMD must act similarly on all housekeeping mRNAs. Indeed, there are no protein bands or protein groups that stand out during the time-dependent progressive loss of translation (Fig. 1C , S1A-B).