RNase-L Control of Cellular mRNAs: Roles in Biologic Functions and Mechanisms of Substrate Targeting

Abstract

RNase-L is a mediator of type 1 interferon-induced antiviral activity that has diverse and critical cellular roles, including the regulation of cell proliferation, differentiation, senescence and apoptosis, tumorigenesis, and the control of the innate immune response. Although RNase-L was originally shown to mediate the endonucleolytic cleavage of both viral and ribosomal RNAs in response to infection, more recent evidence indicates that RNase-L also functions in the regulation of cellular mRNAs as an important mechanism by which it exerts its diverse biological functions. Despite this growing body of work, many questions remain regarding the roles of mRNAs as RNase-L substrates. This review will survey known and putative mRNA substrates of RNase-L, propose mechanisms by which it may selectively cleave these transcripts, and postulate future clinical applications.

Enteropathogenic Escherichia coli Inhibits Type I Interferon- and RNase L-Mediated Host Defense To Disrupt Intestinal Epithelial Cell Barrier Function

“…TTP is an RNA binding protein that binds A-U-rich elements in the 3= untranslated regions of mRNAs encoding TNF-␣ and other proinflammatory mediators to stimulate their degradation (88). Consistent with a role for RNase L in this regulation, the RNase L protein interacts with TTP and downregulates a subset of TTP targets, suggesting that TTP directs RNase L to cleave specific mRNAs (89). The EPEC-induced inhibition of RNase L and enhanced expression of TNF-␣ support this model; however, RNase L negatively regulates TTP mRNA as part of an autoregulatory loop (90), and TTP activity is posttranslationally regulated by p38 in response to inflammatory stimuli (91,92), indicating that a complex regulatory network functions to tightly regulate TNF-␣.…”

A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation

“…RNASEL, which is induced by interferon signaling, nonspecifically degrades both viral and cellular RNA as a step toward cell death (Hassel et al 1993;Castelli et al 1997;Brennan-Laun et al 2014). In contrast, recent studies have shown that 5 ′ exonucleases and decapping machinery selectively target flaviviruses and bunyaviruses, respectively (Hopkins et al 2013(Hopkins et al , 2015Moon and Wilusz 2013).…”

ABCE1 is essential for S phase progression in human cells

“…However, the control of cell proliferation by ABCE1 could be more complex due to its fundamental role in translation as well as implication in the RNase L pathway regulating diverse cellular activities. 13,29 Histone gene expression is restricted to S phase and is regulated by several mechanisms at the transcriptional and post-transcriptional levels. 79,86 Efficient translation of histone mRNAs lacking polyA tails is maintained by their circularized structure, which is stabilized by multiple proteinprotein interactions mediated by SLBP bound to the stemloop sequence at the 3 0 end.…”

“…11 Besides antiviral activity, this pathway plays a more general role in regulation of cellular RNA expression and turnover. 12,13 In contrast to ABCE1, RNase L is present only in vertebrates, implying that ABCE1 must have essential functions not related to the 2-5A pathway.…”