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.

FIG. 1.

(A) Activation of RNase-L-mediated cleavage of substrates by the 2-5A pathway. 2′PDE, 2′-phosphodiesterase; dsRNA, double-stranded RNA; IFN, interferon; p'tase, phosphatase; RLI, RNase-L inhibitor; ssRNA, single-stranded RNA. (B) Map of the domains of RNase-L including 2-5A binding. KEN, kinase-extension nuclease.

FIG. 2.

Models of RNase-L substrate targeting. (A) Localized activation of OAS and RNase-L results in the cleavage of contiguous or proximal RNAs. OAS, 2′,5′-oligoadenylate synthetase. (B) RNase-L-mediated cleavage of polysome-bound RNAs via association with eRF3. PABP, poly-A-binding protein. (C) RNase-L-mediated cleavage is targeted through its interaction with RNABPs (TTP is shown as the RNABP in this figure). 3′UTR, 3′-untranslated region; RNABP, RNA-binding protein; TTP, tristetraprolin.

FIG. 3.

Co-immunoprecipitation (IP) of Myc-tagged RNase-L and FLAG-tagged TTP in 293-T cells using FLAG and IgG control antibodies.