Abstract
The mammalian genome has evolved to encode a battery of mechanisms, to mitigate a progression in the life cycle of an invasive viral pathogen. Although apparently disadvantaged by their dependence on the host biosynthetic processes, an immensely faster rate of evolution provides viruses with an edge in this conflict. In this review, I have discussed the potential anti-virus activity of inositol-requiring enzyme 1 (IRE1), a well characterized effector of the cellular homeostatic response to an overloading of the endoplasmic reticulum (ER) protein-folding capacity. IRE1, an ER-membrane-resident ribonuclease (RNase), upon activation catalyses regulated cleavage of select protein-coding and non-coding host RNAs, using an RNase domain which is homologous to that of the known anti-viral effector RNaseL. The latter operates as part of the Oligoadenylate synthetase OAS/RNaseL system of anti-viral defense mechanism. Protein-coding RNA substrates are differentially treated by the IRE1 RNase to either augment, through cytoplasmic splicing of an intron in the Xbp1 transcript, or suppress gene expression. This referred suppression of gene expression is mediated through degradative cleavage of a select cohort of cellular RNA transcripts, initiating the regulated IRE1-dependent decay (RIDD) pathway. The review first discusses the anti-viral mechanism of the OAS/RNaseL system and evasion tactics employed by different viruses. This is followed by a review of the RIDD pathway and its potential effect on the stability of viral RNAs. I conclude with a comparison of the enzymatic activity of the two RNases followed by deliberations on the physiological consequences of their activation.
Highlights
Establishment of infection by a virus, even in permissive host cells, is beset with a plethora of challenges from innate-antiviral and cell-death pathways
The viral nucleic acids which could be the genome or RNA derived from transcription of the genome [negative-stranded single-sense RNA or double-stranded RNA or DNA virus], offer critical targets for both detection and eradication
The viral nucleic acid targeting armaments in the host arsenal include those that recognize the associated molecular patterns like toll-like receptors (TLRs), DDX58, IFIH1, IFIT proteins [IFN-stimulated genes (ISG)56 and ISF54], etc. (Aoshi et al, 2011; Bowzard et al, 2011; Jensen and Thomsen, 2012). This is followed by IFN signaling and expression or activation of factors that target the inducer for degradation or modification like OAS/ribonuclease L (RNaseL) system, APOBEC3, MCPIP1, the ZC3HAV1/exosome system and RNAi pathways (Gao et al, 2002; Sheehy et al, 2002; Guo et al, 2007; Daffis et al, 2010; Sidahmed and Wilkie, 2010; Schmidt et al, 2012; Cho et al, 2013a; Lin et al, 2013)
Summary
Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Gurgaon, India. IRE1, an ER-membrane-resident ribonuclease (RNase), upon activation catalyses regulated cleavage of select protein-coding and non-coding host RNAs, using an RNase domain which is homologous to that of the known anti-viral effector RNaseL. The latter operates as part of the Oligoadenylate synthetase OAS/RNaseL system of anti-viral defense mechanism. The review first discusses the anti-viral mechanism of the OAS/RNaseL system and evasion tactics employed by different viruses This is followed by a review of the RIDD pathway and its potential effect on the stability of viral RNAs. I conclude with a comparison of the enzymatic activity of the two RNases followed by deliberations on the physiological consequences of their activation
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