Helicases in Antiviral Immunity: Dual Properties as Sensors and Effectors

Abstract

Many helicases have a unique ability to couple cognate RNA binding to ATP hydrolysis, which can induce a large conformational change that affects its interaction with RNA, position along RNA, or oligomeric state. A growing number of these helicases contribute to the innate immune system, either as sensors that detect foreign nucleic acids and/or as effectors that directly participate in the clearance of such foreign species. In this review, we discuss a few examples, including retinoic acid-inducible gene-I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and Dicer, focusing on their dual functions as both sensors and effectors. We will also discuss the closely related, but less understood, helicases, laboratory of genetics and physiology 2 (LGP2) and Dicer-related helicase-1 and -3 (DRH-1 and -3).

Keywords: Dicer; Dicer-like helicase; MDA5; RIG-I; antiviral immunity; helicase.

Fig. 1

Antiviral activities of retinoic acid-inducible gene-I (RIG-I)-like helicases (A) Domain architectures of RIG-I, melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2). CARD refers to the caspase activation recruitment domain. Hel1 and 2 refer to the two conserved RecA-like domains in the DExD/H helicase family. Hel2i is the helicase insertion domain. P stands for the pincer domain. CTD indicates the C-terminal domain. (B) Structures of the CARDs-deletion mutants of MDA5 and RIG-I in complex with dsRNA. The helicase domains, pincer and CTD are colored grey, blue and purple, respectively. The image is adopted from ref (22). (C) The dual functions of RIG-I and MDA5 as canonical pattern recognition receptors (PRRs) that suppress viral replication through the downstream signaling pathway and effectors that directly act against viruses. For the effector functions, ATP-dependent protein displacement activity is summarized on the right side.

Fig. 2

Antiviral activities of Dicers (A) Domain architectures of Dicers from Drosophila melanogaster and Caenorhabditis elegans, and human. Dicer-1 has the truncated Hel1 (indicated by X), thus lacking the functional helicase property. (B) Antiviral activities of Drosophila Dicer-2. Dicer-2 functions as an antiviral effector molecule by cleaving viral dsRNA upon recognition. At the same time, it functions as a PRR-like sensor by having the cleavage product, siRNA, act as a signal to activate the downstream effector, RISC, for gene silencing and the TRAF-Rel2 signaling pathway for expression of Vago. Vago is then secreted and systemically spread to uninfected cells to establish the antiviral response.

Fig. 3

Antiviral activities of Dicer related helicase 1 and 3 (DRH-1 DRH-3) (A) Domain architectures of DRH-1 and -3 from C. elegans. NTD stands for the N-terminal domain. (B) Distinct antiviral activities of C. elegans DRH-1 and -3. DRH-1 assists in Dicer-mediated cleavage of viral dsRNA and biosynthesis of primary siRNA (1° siRNA) against viral RNA. DRH-3, by contrast, participates in amplification of the primary siRNA signal by cooperating with RNA-dependent RNA polymerase (RdRP) in secondary siRNA (2° siRNA) production. The 2° siRNA response can be further amplified by cell-to-cell spread, allowing uninfected cells to bypass primary siRNA production and facilitating secondary siRNA production upon infection (i.e. upon introduction of the template for RdRP).