The interferon-induced enzymes 2'-5'-oligoadenylate synthetase (OAS) and RNase L are
key components of innate immunity involved in sensory and effector functions following
viral infections. Upon binding target RNA, OAS is activated to produce 2'-5'-linked
oligoadenylates (2-5A) that activate RNase L, which then cleaves single-stranded self
and non-self RNA. Modified nucleosides that are present in cellular transcripts have
been shown to suppress activation of several RNA sensors. Here, we demonstrate that
in vitro transcribed, unmodified RNA activates OAS, induces RNase L-mediated ribosomal
RNA (rRNA) cleavage and is rapidly cleaved by RNase L. In contrast, RNA containing
modified nucleosides activates OAS less efficiently and induces limited rRNA cleavage.
Nucleoside modifications also make RNA resistant to cleavage by RNase L. Examining
translation in RNase L-/- cells and mice confirmed that RNase L activity reduces translation
of unmodified mRNA, which is not observed with modified mRNA. Additionally, mRNA containing
the nucleoside modification pseudouridine is translated longer and has an extended
half-life. The observation that modified nucleosides in RNA reduce 2-5A pathway activation
joins OAS and RNase L to the list of RNA sensors and effectors whose functions are
limited when RNA is modified, confirming the role of nucleoside modifications in suppressing
immune recognition of RNA.
