DDX58

DDX58 Full Name

DEAD (Asp-Glu-Ala-Asp) box polypeptide 58

DDX58 Introduction

DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 (DDX58), more commonly known as Retinoic acid-inducible gene I (RIG-I), is a gene that codes for a cytosolic pattern recognition receptor (PRR) of the innate immune system. DDX58 is a member of the DEAD-box helicase superfamily, all proteins of which are characterized by having a conserved Asp-Glu-Ala-Asp (D-E-A-D) motif in their catalytic core, and it was named after this motif. In the field of immunology, however, the gene and its product are more commonly known by the name RIG-I, as they are almost always referred to in the literature. RIG-I was originally discovered as one of several genes which were upregulated in a cell in response to retinoic acid treatment, hence its name. The association between this gene and the immune system was quickly established, however, and the name is a bit of a misnomer. Whereas Toll-like receptors (TLRs) patrol the cell membrane, DDX58 and its homologs patrol the interior of the cell. This allows them to detect any viruses which have successfully entered the cell and are now replicating in the cytoplasm. Activated by its specific pathogen-associated molecular patterns (PAMPs), which are primarily certain RNA structures that can be found in viral genomes or replication intermediates, DDX58 is rapidly activated and initiates strong downstream defense signals that work to clear the infection and prevent it from spreading throughout the body.

Figure 1. Two-pronged antiviral attack by RIG-I. (Source: Weber F. 2015)

The DDX58 protein consists of three main functional domains that work in concert to carry out the entire process from viral RNA recognition to downstream signal transduction. The N-terminal tandem caspase recruitment domains (2CARD) are located at the protein's N-terminus and consist of two CARD domains. In the resting state, these 2CARD domains are masked by other parts of the protein, remaining inactive. Upon activation of DDX58, the 2CARD domains become exposed and act as signaling "adaptors," responsible for homotypic interaction with the CARD domain of the downstream adaptor protein MAVS, thereby passing the signal on. The central domain of DDX58, which houses the DExD/H-box RNA helicase catalytic core domain, is the motor domain of DDX58. This region contains the ATP binding and hydrolysis sites as well as the RNA binding sites. It is the central domain which provides DDX58 with the function of RNA binding and the usage of energy liberated during ATP hydrolysis to walk on the RNA in order to confirm correctness of ligand binding and induce subsequent conformational changes. The C-terminal regulatory domain (CTD), which is also known as the repressor domain (RD), of DDX58 acts as an "intramolecular inhibitor" in the absence of activation in the inactive state. It folds back, interacting with the helicase domain and the 2CARD domains to form a compact, autoinhibited "off" conformation. This prevents the 2CARD domains from contacting downstream molecules and blocks spontaneous activation of the signaling pathway. More importantly, the CTD is the key site for direct recognition of the 5'-triphosphate group on viral RNA.

In order to avoid such excessive immune responses that lead to tissue damage and autoimmune diseases, the DDX58 pathway is under complex and multi-layered negative regulation. Left unchecked, the constant production of Type I interferon would have devastating effects on the organism. Multiple "brakes" on the pathway have been discovered over the years. For example, some deubiquitinating enzymes (DUBs) can cleave off the K63-linked ubiquitin chains from DDX58 or other downstream adaptor proteins, and thereby inactivate the pathway. Additionally, some ISGs themselves can also function in negative feedback, like the ISGs induced by interferon itself (e.g. USP18, SOCS1/3), which can suppress interferon signaling. In an elegant example, one splicing variant of DDX58 gene itself, called PTIR1, was shown to function as an endogenous dominant-negative inhibitor of DDX58. PTIR1 restricts the strength and duration of DDX58 signaling by inhibiting its dimerization, promoting its deubiquitination, and preventing its binding to MAVS.

Alternate Names for DDX58

DDX58; DEAD (Asp-Glu-Ala-Asp) box polypeptide 58; RIGI; RIG-I; RLR-1; probable ATP-dependent RNA helicase DDX58; RNA helicase RIG-I; DEAD box protein 58; retinoic acid-inducible gene 1 protein; retinoic acid-inducible gene I protein; DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide;

• 1. Weber F. The catcher in the RIG-I. Cytokine. 2015 Nov;76(1):38-41.
  2. Thoresen D, et al. The molecular mechanism of RIG-I activation and signaling. Immunol Rev. 2021 Nov;304(1):154-168.