Interferon-Stimulated Genes as Enhancers of Antiviral Innate Immune Signaling

Abstract

The ability of a host to curb a viral infection is heavily reliant on the effectiveness of an initial antiviral innate immune response, resulting in the upregulation of interferon (IFN) and, subsequently, IFN-stimulated genes (ISGs). ISGs serve to mount an antiviral state within a host cell, and although the specific antiviral function of a number of ISGs has been characterized, the function of many of these ISGs remains to be determined. Recent research has uncovered a novel role for a handful of ISGs, some of them directly induced by IFN regulatory factor 3 in the absence of IFN itself. These ISGs, most with potent antiviral activity, are also able to augment varying arms of the innate immune response to viral infection, thereby strengthening this response. This new understanding of the role of ISGs may, in turn, help the recent advancement of novel therapeutics aiming to augment innate signaling pathways in an attempt to control viral infection and pathogenesis.

Keywords: Innate immunity; Interferon; Interferon-stimulated genes; Virus.

Fig. 1

When a virus enters a cell, viral PAMPS are recognized by pattern recognition receptors, and activate a number of signaling cascades that result in the production of type I and III interferon (IFN) and inflammatory cytokines to induce an antiviral state. These pathways are augmented and enhanced by a number of IFN-stimulated genes (ISGs). Protein kinase R (PKR) is a double-stranded RNA receptor pivotal in the activation of MAVS (both following MDA5 activation and independently of MDA5 and RIG-I activation). Zinc-finger antiviral protein S (ZAP-S) enhances RIG-I ATPase activity. Tripartite motif 21 (TRIM21) enhances innate immune signaling in 2 ways: (1) it detects the Fc portion of the antibody bound to nonenveloped viruses entering the cytosol and catalyzes the synthesis of K63-linked polyubiquinated (K63 Ub) chains to activate IRFs and NF-κB, and induce a type I IFN response independently of RIG-I and cGAS; (2) it recruits the proteasome instigating premature virion uncoating, exposing PAMPS to RIG-I and cGAS. TRIM56 acts as a scaffold protein promoting IRF3 activation by enhancing the efficient interaction of STING and TBK1 and via an interaction with TRIF. Viperin enhances the K63-linked ubiquitination of IRAK1 by promoting an interaction between IRAK1 and TRAF6. DDX60 can bind dsRNA, and it associates with both RIG-I and MDA5 to enhance their activation.

Fig. 2

Protein domains for interferon (IFN)-stimulated genes (ISGs) able to positively augment the type I IFN response. PKR, protein kinase R; ZAP, zinc-finger antiviral protein; ZAP-L, long ZAP isoform; ZAP-S, short ZAP isoform; TRIM, tripartite motif; DDX60, DExD/H box helicase 60; PARP, poly(ADP-ribose) polymerase; RING, really interesting new gene; SAM, S-adenosyl methionine; WWE, W and E residues; aa, amino acids.