Pathologic effects of RNase-L dysregulation in immunity and proliferative control

Abstract

The endoribonuclease RNase-L is the terminal component of an RNA cleavage pathway that mediates antiviral, antiproliferative and immunomodulatory activities. Inactivation or dysregulation of RNase-L is associated with a compromised immune response and increased risk of cancer, accordingly its activity is tightly controlled and requires an allosteric activator, 2',5'-linked oligoadenylates, for enzymatic activity. The biological activities of RNase-L are a result of direct and indirect effects of RNA cleavage and microarray analyses have revealed that RNase-L impacts the gene expression program at multiple levels. The identification of RNase-L-regulated RNAs has provided insights into potential mechanisms by which it exerts antiproliferative, proapoptotic, senescence-inducing and innate immune activities. RNase-L protein interactors have been identified that serve regulatory functions and are implicated as alternate mechanisms of its biologic functions. Thus, while the molecular details are understood for only a subset of RNase-L activities, its regulation by small molecules and critical roles in host defense and as a candidate tumor suppressor make it a promising therapeutic target.

Figure 1

The 2-5A System. IFN treatment (shown) or antiproliferative or microbial stimuli induce the transcription of OAS genes; in the presence of dsRNA, OAS proteins are activated to produce 2-5A; 2-5A binds and activates latent RNase-L resulting in the cleavage of ssRNA. 2-5A system activity is attenuated by the 2'-phosphodiesterase-mediated degradation of 2-5A and inhibition of RNase-L by RLI.

Figure 2

RNase-L domain structure and model of activation. A. The functional domains of RNase-L protein and corresponding amino acids are shown. B. Model of 2-5A-induced conformational changes that result in RNase-L dimerization and activation of enzymatic activity.

Figure 3

Working model depicting the mechanisms of RNase-L action in host defense and proliferative control. As discussed in the text, direct and indirect effects of RNA cleavage mediate the biological activities of RNase-L. RNase-L-protein interactions may also contribute to these functions (dotted line). Disruption of RNase-L expression or activity is associated with pathologic conditions including increased susceptibility to pathogens, dysregulated immune responses, and an altered proliferative phenotype. Steps leading to 2-5A production are not included in the diagram and RNase-L is shown in its activated form.