Can't RIDD off viruses

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.

Keywords: IRE1; OAS; RIDD pathway; RNaseL; UPR; Xbp1; unfolded protein response.

FIGURE 1

Schematic representation of the ribonuclease activity of IRE1 and RNaseL showing cross-talk between the paths catalysed by the enzymes. The figure shows activation of RNase activity following dimerization triggered by either accumulation of unfolded proteins in the ER-lumen or synthesis of 2–5A by the enzyme OAS, respectively, for IRE1 and RNaseL. The cleavage of Xbp1u by IRE1 releases an intron thus generating Xbp1s. The IRE1 targets in RIDD pathway or all RNaseL substrates are shown to undergo degradative cleavage. The cleavage products generated through degradation of the respective substrate is shown to potentially interact with RIG-I thereby leading to Interferon secretion and trans-activation of Oas genes through Interferon signaling. Abbreviations: RIG-I = retinoic acid inducible gene-I, Ifnb = interferon beta gene loci, IFN = interferons, ISG = interferon-sensitive genes, 2–5A = 2′–5′ oligoadenylates.

FIGURE 2

Schematic representation of distinct protein domains in human RNaseL and IRE1. (A) The domains homologous between RNaseL and IRE1 are shaded identically. The domain name abbreviations denote the following: ARD = ankyrin repeat domain; LD = luminal domain; PK = protein kinase domain; KEN = kinase extension nuclease domain. The amino acid positions bordering each domain are numbered. The schematic drawings are not according to scale. (B) ClustalW alignment of primary sequence from a segment of the PK domain indicating amino acid residues which are important for interacting with nucleotide cofactors. The conserved lysine residues, critical for this interaction (K599 for IRE1 and K392 in RNaseL) are underlined. (C) Alignment of the KEN domains in RNaseL and IRE1. The amino acids highlighted and numbered in IRE1 are critical for the IRE1 RNase activity (Tirasophon et al., 2000).