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

2-5AMD requires the coordinated activity of 2-5A oligonucleotide synthetases (OASs) and the pseudokinase-endoribonuclease, RNase L. The action of the OASs closely parallels that action of a structurally similar dsDNA sensor cGAS. cGAS synthesizes a second messenger cGAMP (cyclic-G 2',5' A 3',5' p) to activate the IFN response via the cGAMP receptor, STING (Civril et al., 2013) . The OASs use the same mechanism of regulation, but function as sensors of dsRNA (Civril et al., 2013; Donovan et al., 2013) . The OASs synthesize the second messenger 2-5A (5'-ppp-A 2'p5' A( 2'p5' A) n≥0 ) facilitates its dimerization and high-order oligomerization, which provides the switch for activation of RNA cleavage by 2-5AMD (Han et al., 2014; Han et al., 2012) . Upon activation, RNase L cleaves single-stranded RNA molecules at UN^N sites (Floyd-Smith et al., 1981; Han et al., 2014) . The prevalence of this short motif results in 2-5AMD sensitivity of many tRNAs, rRNAs, mRNAs, Y-RNAs and vault RNAs (Cooper et al., 2014b; . During homeostasis, 2-5AMD regulates adhesion and migration activity of mammalian cells (Banerjee et al., 2015; Rath et al., 2015) . Upon acute activation by dsRNA, 2-5AMD arrests global translation by an immediate and poorly understood mechanism (Alisha Chitrakar et al., 2018; . In mammalian cells, dsRNA inhibits translation not only via 2-5AMD, but also via phosphorylation of the translation initiation factor eIF2 by the serine-threonine kinase protein kinase R (PKR) (Fig. 1A ). 2-5AMD and the PKR pathway are separated in time and in A549 human lung epithelial cells, 2-5AMD is the only mechanism responsible for the rapid translational inhibition .