Entry - *609631 - RNA SENSOR RIGI; RIGI - OMIM - (OMIM.ORG)

 
 
* 609631

RNA SENSOR RIGI; RIGI


Alternative titles; symbols

RETINOIC ACID-INDUCIBLE GENE I
DExD/H-BOX HELICASE 58; DDX58
DEAD-BOX POLYPEPTIDE 58
DEAD/H-BOX 58


HGNC Approved Gene Symbol: RIGI

Cytogenetic location: 9p21.1   Genomic coordinates (GRCh38) : 9:32,455,302-32,526,196 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
9p21.1 Singleton-Merten syndrome 2 616298 AD 3

TEXT

▼ Description

RIGI, or DDX58, is an RNA helicase that belongs to the DEAD/H box family. Members of the DEAD/H box family have diverse roles in regulating gene expression and cellular processes (Imaizumi et al., 2002).


▼ Cloning and Expression

Using subtractive hybridization to identify lipopolysaccharide (LPS)-inducible genes in endothelial cells, followed by RACE, Imaizumi et al. (2002) isolated a cDNA encoding RIGI. Imaizumi et al. (2002) noted that RIGI had been identified in 1997 as a retinoic acid-inducible gene in a promyelocytic leukemia cell line (GenBank AF038963). The predicted 925-amino acid protein has a calculated molecular mass of 101 kD and belongs to the DEAD/H box family. RIGI contains a GxGKT motif, suggesting it is an RNA helicase. Northern blot analysis of endothelial cells detected a 3.0-kb transcript only after LPS stimulation.

Yoneyama et al. (2004) noted that RIGI has 2 copies of a caspase recruitment domain (CARD) at its N terminus in addition to its C-terminal helicase domain.


▼ Mapping

Gross (2012) mapped the DDX58 gene to chromosome 9p21.1 based on an alignment of the DDX58 sequence (GenBank AF038963) with the genomic sequence (GRCh37).

▼ Gene Function

Using subtractive hybridization, Imaizumi et al. (2002) showed that LPS-stimulated endothelial cells expressed RIGI and COX2 (PTSG2; 600262). Northern blot, Western blot, and RT-PCR analyses showed that RIGI mRNA and protein were expressed in endothelial cells only after LPS stimulation in a concentration-dependent manner. Overexpression of RIGI selectively upregulated expression of COX2 mRNA and protein in transfected bladder cancer cells and induced COX2 promoter activity in endothelial cells.

By RT-PCR and Western blot analysis, Imaizumi et al. (2004) showed that gamma-interferon (IFNG; 147570)-stimulated umbilical artery smooth muscle cells (SMCs) expressed RIGI mRNA and protein. Immunohistochemical and confocal microscopy analyses by Imaizumi et al. (2004) demonstrated cytoplasmic expression of RIGI in SMCs in vivo. Further immunoblot and microscopic analyses indicated that IFNG stimulated expression of RIGI in umbilical vein. RIGI expression was also detected in normal human pulmonary endothelial cells.

Cui et al. (2004) detected RIGI expression in an IFNG-stimulated breast cancer cell line. Overexpression of RIGI upregulated expression of ISG15 (G1P2; 147571).

Yoneyama et al. (2004) showed that double-stranded RNA (dsRNA) induced RIGI expression in an ATPase-dependent manner and augmented production of type I interferon (e.g., IFNB; 147640). A truncated form of RIGI lacking the helicase domain but containing the tandem CARD motifs transduced signals leading to activation of IRF3 (603734) and NFKB (see 164011). Using RNA interference, Yoneyama et al. (2004) found that RIGI was essential for virus-induced expression of IRF3. They concluded that RIGI is essential for detection and eradication of replicating viral genomes.

Using a hepatitis C virus (HCV; see 609532) replicon-expressing cell line, Breiman et al. (2005) showed that the HCV NS3/4A protease impaired IFNB production in both TRIF (TICAM1; 607601)-dependent and TRIF-independent pathways. They demonstrated that impairment of the TRIF-independent pathway resulted from inhibition of RIGI-mediated IFNB promoter activation by NS3/4A. Breiman et al. (2005) proposed that RIGI is a key factor in the TRIF-independent, NS3/4A-sensitive pathway of IFNB activation.

Li et al. (2005) found that hepatoma cells did not show Toll-like receptor-3 (TLR3; 603029)-dependent IFNB activation in response to a dsRNA analog, poly(I-C), whereas nonneoplastic hepatocytes showed robust TLR3-dependent IFNB expression in response to poly(I-C). In contrast to poly(I-C), both hepatoma and normal hepatocyte cell lines produced IFNB in response to Sendai virus in a TLR3-independent, RIGI-dependent manner. Silencing of RIGI expression impaired the response to Sendai virus, but not to poly(I-C). Li et al. (2005) concluded that hepatocytes contain 2 distinct antiviral signaling pathways leading to type I interferon expression, one dependent upon TLR3 and the other dependent upon RIGI.

Hornung et al. (2006) demonstrated that the 5-prime-triphosphate end of RNA generated by viral polymerases is responsible for RIGI-mediated detection of RNA molecules. Detection of 5-prime-triphosphate RNA is abrogated by capping of the 5-prime-triphosphate end or by nucleoside modification of RNA, both occurring during posttranscriptional RNA processing in eukaryotes. Genomic RNA prepared from a negative-strand RNA virus and RNA prepared from virus-infected cells (but not from noninfected cells) triggered a potent interferon-alpha (see IFNA; 147660) response in a phosphatase-sensitive manner. Five-prime-triphosphate RNA directly binds to RIGI. Thus, uncapped 5-prime-triphosphate RNA (termed 3pRNA) present in viruses known to be recognized by RIGI, but absent in viruses known to be detected by MDA5 (606951), such as the picornaviruses, serves as the molecular signature for the detection of viral infection by RIGI.

Pichlmair et al. (2006) showed that influenza A virus infection does not generate dsRNA and that RIGI is activated by viral genomic single-stranded RNA (ssRNA) bearing 5-prime-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIGI in infected cells. Pichlmair et al. (2006) concluded that these results identified RIGI as a ssRNA sensor and potential target of viral immune evasion and suggested that its ability to sense 5-prime-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.

Gack et al. (2007) reported that the N-terminal caspase recruitment domains (CARDs) of RIGI undergo robust ubiquitination induced by TRIM25 (600453) in mammalian cells. The C-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIGI; this interaction effectively delivers the lys63-linked ubiquitin moiety to the N-terminal CARDs of RIGI, resulting in a marked increase in RIGI downstream signaling activity. The lys172 residue of RIGI is critical for efficient TRIM25-mediated ubiquitination and for MAVS (609676) binding, as well as the ability of RIGI to induce antiviral signal transduction. Gene targeting demonstrated that TRIM25 is essential not only for RIGI ubiquitination but also for RIGI-mediated interferon-beta production and antiviral activity in response to RNA virus infection. Thus, Gack et al. (2007) demonstrated that TRIM25 E3 ubiquitin ligase induces the lys63-linked ubiquitination of RIGI, which is crucial for the cytosolic RIGI signaling pathway to elicit host antiviral innate immunity.

Using yeast 2-hybrid analysis, Arimoto et al. (2007) isolated RNF125 (610432) as a ubiquitin-like protein with E3-ligase activity that interacted with the E2 enzyme UBCH8 (UBE2L6; 603890). In addition, they found that RIGI interacted with UBCH8 and RNF125. Interaction of RIGI with RNF125 required the CARD domain and C-terminal region of RIGI. Downregulation of RNF125 by small interfering RNA reduced the levels of RIGI and prevented RIGI polyubiquitination. Mutation of cys72 and cys75 of RNF125 to ala abolished its ability to mediate RIGI ubiquitination. IFNA upregulated expression of RNF125, UBCH5 (UBE2D1; 602961), and RIGI. Arimoto et al. (2007) concluded that RNF125 ubiquitination function serves as a negative regulatory route for IFN production.

Saito et al. (2007) found that RIGI and LGP2 (608588), but not MDA5, efficiently bound HCV RNA to confer IFNB expression. After HCV infection and RNA binding, RIGI shifted from a monomer to a self-associating protein that also interacted through its CARD domain with IPS1 (HISPPD2A; 610979) to signal IRF3- and NFKB-responsive genes. Mutation analysis showed that a RIGI C-terminal repressor domain (RD) was required for RIGI multimerization and IPS1 interaction. Deletion of the RD resulted in constitutive signaling to the IFNB promoter, whereas expression of the RD alone prevented signaling and increased cellular permissiveness to HCV. Saito et al. (2007) identified an analogous RD in LGP2 that interacted in trans with RIGI to ablate self-association and signaling. They concluded that RIGI is a pathogen recognition receptor for HCV and that its RD is a key modulator of host defenses controlling HCV infection and production. Saito et al. (2007) proposed that modulation of RIGI/LGP2 interaction dynamics may have therapeutic implications for immune regulation.

By RT-PCR, Western blot, and fluorescence microscopy analyses, Zhang et al. (2008) detected increased expression of RIGI in human and mouse myeloid leukemia cells upon retinoic acid-induced terminal granulocytic differentiation, suggesting that RIGI expression is developmentally regulated along with myeloid differentiation. Mice lacking Rigi developed progressive granulocytosis and chronic myeloid leukemia (see CML; 608232). The progressive granulopoiesis was associated with reduced expression of Icsbp1 (601565). Zhang et al. (2008) concluded that RIGI has a critical regulatory role in modulating the generation and differentiation of granulocytes.

RIGI is a cytosolic multidomain protein that detects viral RNA and elicits an antiviral immune response. Two N-terminal CARD domains transmit the signal, and the regulatory domain prevents signaling in the absence of viral RNA. Five-prime-triphosphate and dsRNA are 2 molecular patterns that enable RIGI to discriminate pathogenic from self-RNA. Using single-molecule protein-induced fluorescence enhancement, Myong et al. (2009) discovered a robust adenosine 5-prime triphosphate-powered dsRNA translocation activity of RIGI. The CARDs dramatically suppress translocation in the absence of 5-prime-triphosphate, and the activation by 5-prime-triphosphate triggers RIGI to translocate preferentially on dsRNA in cis. Myong et al. (2009) concluded that this functional integration of 2 RNA molecular patterns may provide a means to specifically sense and counteract replicating viruses.

Oshiumi et al. (2010) stated that RIPLET (RNF135; 611358) mediates lys63-linked polyubiquitination of the RIGI C-terminal repressor domain and N-terminal CARDs. They found that fibroblasts, macrophages, and dendritic cells from Riplet -/- mice were defective for production of IFN and other cytokines in response to infection with RNA viruses, but not DNA viruses. The lack of Riplet abolished Rigi activation during RNA virus infection, and Riplet -/- mice were more susceptible to vesicular stomatitis virus infection. Oshiumi et al. (2010) concluded that RIPLET is essential for regulating the RIGI-mediated innate immune response against RNA virus infection in vivo.

Kok et al. (2011) noted that RIGI shares structural similarity with DICER (606241), an RNase III-type nuclease that mediates RNA interference and requires dsRNA-binding partners, such as PACT (PRKRA; 603424), for optimal activity. They showed that PACT physically bound to the C-terminal repression domain of RIGI and stimulated RIGI-induced type I IFN production. PACT potentiated RIGI activation by poly(I:C) and helped sustain antiviral responses. Kok et al. (2011) concluded that PACT has an important role in initiating and sustaining RIGI-dependent antiviral responses.

Goubau et al. (2014) showed that RIGI, encoded by DDX58, mediates antiviral responses to RNAs bearing 5-prime-diphosphates (5-prime-pp) as well as those bearing 5-prime-triphosphates (5-prime-ppp). Genomes from mammalian reoviruses with 5-prime-pp termini, 5-prime-pp RNA isolated from yeast L-A virus, and base-paired 5-prime-pp RNAs made by in vitro transcription or chemical synthesis all bind to RIGI and serve as RIGI agonists. Furthermore, a RIGI-dependent response to 5-prime-pp RNA is essential for controlling reovirus infection in cultured cells and in mice. Goubau et al. (2014) concluded that the minimal determinant for RIGI recognition is a base-paired RNA with 5-prime-pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5-prime-pp RNA, like that of 5-prime-ppp RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.

Mutations in TDP43 (TARDBP; 605078), including ala315-to-thr (A315T; 605078.0009), are a rare cause of amyotrophic lateral sclerosis (ALS10; 612069). However, pathology of TDP43, which encodes an RNA-binding ribonuclear protein involved in RNA processing, is common to over 95% of ALS cases. Transgenic Tdp43 A315T mice develop age-dependent motor neuron degeneration and serve as a model for ALS. Using translating ribosome affinity purification and microarray analysis, MacNair et al. (2016) found that several mRNAs were abnormally regulated in 10-month-old symptomatic Tdp43 A315T mice compared with wildtype controls and 5-month-old presymptomatic Tdp32 A315T mice. Among the misregulated mRNAs was Ddx58, which was upregulated over 2-fold in mutant mice. Immunohistochemical analysis showed abnormally elevated Ddx58 expression in cytoplasm of motor neurons in 10-month-old Tdp43 A315T mice. Expression of human DDX58 was also upregulated in motor neurons and surrounding glial cells in spinal cords of sporadic and familial ALS patients. RNA immunoprecipitation analysis showed that Ddx58 was a direct target of Tdp43 in transfected mouse neuroblastoma cells.


▼ Biochemical Features

Crystal Structure

To understand the synergy between the helicase and the repressor domain for RNA binding, and the contribution of ATP hydrolysis to RIGI activation, Jiang et al. (2011) determined the structure of the human RIGI helicase repressor domain in complex with dsRNA and an ATP analog. The helicase repressor domain organizes into a ring around dsRNA, capping one end, while contacting both strands using previously uncharacterized motifs to recognize dsRNA. Small-angle x-ray scattering, limited proteolysis, and differential scanning fluorimetry indicated that RIGI is in an extended and flexible conformation that compacts upon binding RNA. These results provided a detailed view of the role of helicase in dsRNA recognition, the synergy between the repressor domain and the helicase for RNA binding, and the organization of full-length RIGI bound to dsRNA, and provided evidence of a conformational change upon RNA binding. The RIGI helicase repressor domain structure is consistent with dsRNA translocation without unwinding and cooperative binding to RNA. The structure yielded unprecedented insight into innate immunity and had a broader impact on other areas of biology, including RNA interference and DNA repair, which utilize homologous helicase domains with DICER (606241) and FANCM (609644).

Peisley et al. (2014) reported the crystal structure of the tetramer of human RIGI tandem caspase activation and recruitment domain (2CARD) bound by 3 chains of lys63-linked diubiquitin (K63-Ub2). 2CARD assembles into a helical tetramer resembling a 'lock-washer,' in which the tetrameric surface serves as a signaling platform for recruitment and activation of the downstream signaling molecule, MAVS (609676). Ubiquitin chains are bound along the outer rim of the helical trajectory, bridging adjacent subunits of 2CARD and stabilizing the 2CARD tetramer. The combination of structural and functional analyses revealed that binding avidity dictates the K63-linkage and chain-length specificity of 2CARD, and that covalent ubiquitin conjugation of 2CARD further stabilizes the Ub-2CARD interaction and thus the 2CARD tetramer.


▼ Molecular Genetics

Singleton-Merten Syndrome 2

In a large 4-generation Korean family with glaucoma, aortic and valvular calcification, and skeletal anomalies (SGMRT2; 616298), Jang et al. (2015) identified heterozygosity for a missense mutation in the DDX58 gene (E373A; 609631.0001) that segregated with disease. Affected individuals in another Korean family with SGMRT2 who exhibited only glaucoma and skeletal anomalies were heterozygous for a different missense mutation in DDX58 (C268F; 609631.0002). Functional analysis revealed that both mutations confer constitutive activation and result in increased interferon activity and interferon-stimulated gene expression.

Associations Pending Confirmation

Because of the 2 to 10% primary failure rate of measles vaccination and the importance of innate immunity to prevent or reduce viral replication and spread until the adaptive immune response to eliminate the virus, Haralambieva et al. (2011) performed a comprehensive candidate gene association study in a racially diverse cohort of 745 healthy schoolchildren in Minnesota who had had 2 doses of measles vaccine. Variants within DDX58 were associated with measles-specific antibody variations in Caucasians. Four DDX58 polymorphisms in high linkage disequilibrium were also associated with variations in measles-specific IFNG and IL2 (147680) secretion in Caucasians. ADAR (146920) variants also had a role in regulating measles-specific IFNG responses in Caucasians. Two intronic OAS1 (164350) SNPs were associated with increased neutralizing antibody levels in African Americans. Haralambieva et al. (2011) concluded that multiple innate immunity genes and genetic variants are likely involved in modulating the adaptive immune response to live attenuated measles vaccine in Caucasians and African Americans.


▼ Animal Model

Kato et al. (2005) generated Rigi-deficient mice and, using cells from these mice, found that Rigi, and not the TLR system, played an essential role in antiviral responses in fibroblasts and conventional dendritic cells (DCs). In contrast, antiviral responses in plasmacytoid DCs, which produce abundant IFNA (147660), used the TLR system, principally Tlr7 (300365) and Tlr9 (605474), rather than Rigi. The Rigi -/- mice rarely survived until birth, and histologic examination of embryonic day-12.5 mice showed massive liver degeneration. Survivors had retarded growth and died within 3 weeks after birth.

Using mice deficient in MDA5 (606951), Kato et al. (2006) showed that MDA5 and RIG1 recognize different types of double-stranded RNAs: MDA5 recognizes polyinosine-polycytidylic acid and RIG1 detects in vitro transcribed double-stranded RNAs. RNA viruses are also differentially recognized by RIG1 and MDA5. Kato et al. (2006) found that RIG1 is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus, and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, Rig1-null and Mda5-null mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Kato et al. (2006) concluded that, taken together, their data show that RIG1 and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.


▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 SINGLETON-MERTEN SYNDROME 2

RIGI, GLU373ALA
  
RCV000169760

In affected members of a large 4-generation Korean family with glaucoma, aortic and valvular calcification, and skeletal anomalies (SGMRT2; 616298), Jang et al. (2015) identified heterozygosity for a c.1118A-C transversion (c.1118A-C, NM_014314.3) in the DDX58 gene, resulting in a glu373-to-ala (E373A) substitution at a highly conserved residue within the Hel-1 core helicase domain. The mutation was not found in 500 Korean controls or in 13,006 chromosomes in the NHLBI Exome Variant Server database. Functional analysis in transfected HEK293FT cells demonstrated constitutive activation with the E383A mutant, resulting in increased interferon activity and interferon-stimulated gene expression. Human trabecular meshwork cells transduced with E383A showed cytopathic effects and a significant decrease in cell number compared to controls.


.0002 SINGLETON-MERTEN SYNDROME 2

RIGI, CYS268PHE
  
RCV000169761

In a 20-year-old Korean woman, her mother, and her maternal grandmother, who all had glaucoma and skeletal anomalies (SGMRT2; 616298), Jang et al. (2015) identified heterozygosity for a c.803G-T transversion (c.803G-T, NM_014314.3) in the DDX58 gene, resulting in a cys268-to-phe (C268F) substitution at a highly conserved residue within the Hel-1 core helicase domain. The mutation was not found in 500 Korean controls or in 13,006 chromosomes in the NHLBI Exome Variant Server database. Functional analysis in transfected HEK293FT cells demonstrated constitutive activation with the C268F mutant, resulting in increased interferon activity and interferon-stimulated gene expression. Human trabecular meshwork cells transduced with C268F showed cytopathic effects and a significant decrease in cell number compared to controls.


▼ REFERENCES

  1. Arimoto, K., Takahashi, H., Hishiki, T., Konishi, H., Fujita, T., Shimotohno, K. Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc. Nat. Acad. Sci. 104: 7500-7505, 2007. [PubMed: 17460044, images, related citations] [Full Text]

  2. Breiman, A., Grandvaux, N., Lin, R., Ottone, C., Akira, S., Yoneyama, M., Fujita, T., Hiscott, J., Meurs, E. F. Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKK-epsilon. J. Virol. 79: 3969-3978, 2005. [PubMed: 15767399, images, related citations] [Full Text]

  3. Cui, X.-F., Imaizumi, T., Yoshida, H., Borden, E. C., Satoh, K. Retinoic acid-inducible gene-I is induced by interferon-gamma and regulates the expression of interferon-gamma stimulated gene 15 in MCF-7 cells. Biochem. Cell Biol. 82: 401-405, 2004. [PubMed: 15181474, related citations] [Full Text]

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  9. Imaizumi, T., Aratani, S., Nakajima, T., Carlson, M., Matsumiya, T., Tanji, K., Ookawa, K., Yoshida, H., Tsuchida, S., McIntyre, T. M., Prescott, S. M., Zimmerman, G. A., Satoh, K. Retinoic-acid inducible gene-I is induced in endothelial cells by LPS and regulates expression of COX-2. Biochem. Biophys. Res. Commun. 292: 274-279, 2002. [PubMed: 11890704, related citations] [Full Text]

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Contributors:
Patricia A. Hartz - updated : 02/16/2016
Marla J. F. O'Neill - updated : 4/7/2015
Ada Hamosh - updated : 11/4/2014
Ada Hamosh - updated : 5/29/2014
Matthew B. Gross - updated : 7/20/2012
Paul J. Converse - updated : 7/3/2012
Paul J. Converse - updated : 3/1/2012
Ada Hamosh - updated : 1/3/2012
Paul J. Converse - updated : 4/23/2009
Ada Hamosh - updated : 3/17/2009
Paul J. Converse - updated : 8/23/2007
Paul J. Converse - updated : 6/19/2007
Ada Hamosh - updated : 5/29/2007
Ada Hamosh - updated : 1/10/2007
Ada Hamosh - updated : 6/1/2006
Creation Date:
Paul J. Converse : 10/5/2005
Edit History:
carol : 05/27/2025
mgross : 12/10/2024
mgross : 07/14/2020
mgross : 02/16/2016
carol : 4/7/2015
mcolton : 4/7/2015
alopez : 11/4/2014
alopez : 5/29/2014
mgross : 7/20/2012
mgross : 7/20/2012
terry : 7/3/2012
mgross : 5/8/2012
terry : 3/1/2012
alopez : 1/6/2012
terry : 1/3/2012
mgross : 4/30/2009
terry : 4/23/2009
alopez : 3/23/2009
terry : 3/17/2009
mgross : 8/23/2007
mgross : 6/20/2007
mgross : 6/19/2007
alopez : 6/12/2007
terry : 5/29/2007
alopez : 1/11/2007
terry : 1/10/2007
alopez : 6/3/2006
terry : 6/1/2006
mgross : 10/5/2005
mgross : 10/5/2005
mgross : 10/5/2005

* 609631

RNA SENSOR RIGI; RIGI


Alternative titles; symbols

RETINOIC ACID-INDUCIBLE GENE I
DExD/H-BOX HELICASE 58; DDX58
DEAD-BOX POLYPEPTIDE 58
DEAD/H-BOX 58


HGNC Approved Gene Symbol: RIGI

Cytogenetic location: 9p21.1   Genomic coordinates (GRCh38) : 9:32,455,302-32,526,196 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
9p21.1 Singleton-Merten syndrome 2 616298 Autosomal dominant 3

TEXT

Description

RIGI, or DDX58, is an RNA helicase that belongs to the DEAD/H box family. Members of the DEAD/H box family have diverse roles in regulating gene expression and cellular processes (Imaizumi et al., 2002).


Cloning and Expression

Using subtractive hybridization to identify lipopolysaccharide (LPS)-inducible genes in endothelial cells, followed by RACE, Imaizumi et al. (2002) isolated a cDNA encoding RIGI. Imaizumi et al. (2002) noted that RIGI had been identified in 1997 as a retinoic acid-inducible gene in a promyelocytic leukemia cell line (GenBank AF038963). The predicted 925-amino acid protein has a calculated molecular mass of 101 kD and belongs to the DEAD/H box family. RIGI contains a GxGKT motif, suggesting it is an RNA helicase. Northern blot analysis of endothelial cells detected a 3.0-kb transcript only after LPS stimulation.

Yoneyama et al. (2004) noted that RIGI has 2 copies of a caspase recruitment domain (CARD) at its N terminus in addition to its C-terminal helicase domain.


Mapping

Gross (2012) mapped the DDX58 gene to chromosome 9p21.1 based on an alignment of the DDX58 sequence (GenBank AF038963) with the genomic sequence (GRCh37).

Gene Function

Using subtractive hybridization, Imaizumi et al. (2002) showed that LPS-stimulated endothelial cells expressed RIGI and COX2 (PTSG2; 600262). Northern blot, Western blot, and RT-PCR analyses showed that RIGI mRNA and protein were expressed in endothelial cells only after LPS stimulation in a concentration-dependent manner. Overexpression of RIGI selectively upregulated expression of COX2 mRNA and protein in transfected bladder cancer cells and induced COX2 promoter activity in endothelial cells.

By RT-PCR and Western blot analysis, Imaizumi et al. (2004) showed that gamma-interferon (IFNG; 147570)-stimulated umbilical artery smooth muscle cells (SMCs) expressed RIGI mRNA and protein. Immunohistochemical and confocal microscopy analyses by Imaizumi et al. (2004) demonstrated cytoplasmic expression of RIGI in SMCs in vivo. Further immunoblot and microscopic analyses indicated that IFNG stimulated expression of RIGI in umbilical vein. RIGI expression was also detected in normal human pulmonary endothelial cells.

Cui et al. (2004) detected RIGI expression in an IFNG-stimulated breast cancer cell line. Overexpression of RIGI upregulated expression of ISG15 (G1P2; 147571).

Yoneyama et al. (2004) showed that double-stranded RNA (dsRNA) induced RIGI expression in an ATPase-dependent manner and augmented production of type I interferon (e.g., IFNB; 147640). A truncated form of RIGI lacking the helicase domain but containing the tandem CARD motifs transduced signals leading to activation of IRF3 (603734) and NFKB (see 164011). Using RNA interference, Yoneyama et al. (2004) found that RIGI was essential for virus-induced expression of IRF3. They concluded that RIGI is essential for detection and eradication of replicating viral genomes.

Using a hepatitis C virus (HCV; see 609532) replicon-expressing cell line, Breiman et al. (2005) showed that the HCV NS3/4A protease impaired IFNB production in both TRIF (TICAM1; 607601)-dependent and TRIF-independent pathways. They demonstrated that impairment of the TRIF-independent pathway resulted from inhibition of RIGI-mediated IFNB promoter activation by NS3/4A. Breiman et al. (2005) proposed that RIGI is a key factor in the TRIF-independent, NS3/4A-sensitive pathway of IFNB activation.

Li et al. (2005) found that hepatoma cells did not show Toll-like receptor-3 (TLR3; 603029)-dependent IFNB activation in response to a dsRNA analog, poly(I-C), whereas nonneoplastic hepatocytes showed robust TLR3-dependent IFNB expression in response to poly(I-C). In contrast to poly(I-C), both hepatoma and normal hepatocyte cell lines produced IFNB in response to Sendai virus in a TLR3-independent, RIGI-dependent manner. Silencing of RIGI expression impaired the response to Sendai virus, but not to poly(I-C). Li et al. (2005) concluded that hepatocytes contain 2 distinct antiviral signaling pathways leading to type I interferon expression, one dependent upon TLR3 and the other dependent upon RIGI.

Hornung et al. (2006) demonstrated that the 5-prime-triphosphate end of RNA generated by viral polymerases is responsible for RIGI-mediated detection of RNA molecules. Detection of 5-prime-triphosphate RNA is abrogated by capping of the 5-prime-triphosphate end or by nucleoside modification of RNA, both occurring during posttranscriptional RNA processing in eukaryotes. Genomic RNA prepared from a negative-strand RNA virus and RNA prepared from virus-infected cells (but not from noninfected cells) triggered a potent interferon-alpha (see IFNA; 147660) response in a phosphatase-sensitive manner. Five-prime-triphosphate RNA directly binds to RIGI. Thus, uncapped 5-prime-triphosphate RNA (termed 3pRNA) present in viruses known to be recognized by RIGI, but absent in viruses known to be detected by MDA5 (606951), such as the picornaviruses, serves as the molecular signature for the detection of viral infection by RIGI.

Pichlmair et al. (2006) showed that influenza A virus infection does not generate dsRNA and that RIGI is activated by viral genomic single-stranded RNA (ssRNA) bearing 5-prime-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIGI in infected cells. Pichlmair et al. (2006) concluded that these results identified RIGI as a ssRNA sensor and potential target of viral immune evasion and suggested that its ability to sense 5-prime-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.

Gack et al. (2007) reported that the N-terminal caspase recruitment domains (CARDs) of RIGI undergo robust ubiquitination induced by TRIM25 (600453) in mammalian cells. The C-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIGI; this interaction effectively delivers the lys63-linked ubiquitin moiety to the N-terminal CARDs of RIGI, resulting in a marked increase in RIGI downstream signaling activity. The lys172 residue of RIGI is critical for efficient TRIM25-mediated ubiquitination and for MAVS (609676) binding, as well as the ability of RIGI to induce antiviral signal transduction. Gene targeting demonstrated that TRIM25 is essential not only for RIGI ubiquitination but also for RIGI-mediated interferon-beta production and antiviral activity in response to RNA virus infection. Thus, Gack et al. (2007) demonstrated that TRIM25 E3 ubiquitin ligase induces the lys63-linked ubiquitination of RIGI, which is crucial for the cytosolic RIGI signaling pathway to elicit host antiviral innate immunity.

Using yeast 2-hybrid analysis, Arimoto et al. (2007) isolated RNF125 (610432) as a ubiquitin-like protein with E3-ligase activity that interacted with the E2 enzyme UBCH8 (UBE2L6; 603890). In addition, they found that RIGI interacted with UBCH8 and RNF125. Interaction of RIGI with RNF125 required the CARD domain and C-terminal region of RIGI. Downregulation of RNF125 by small interfering RNA reduced the levels of RIGI and prevented RIGI polyubiquitination. Mutation of cys72 and cys75 of RNF125 to ala abolished its ability to mediate RIGI ubiquitination. IFNA upregulated expression of RNF125, UBCH5 (UBE2D1; 602961), and RIGI. Arimoto et al. (2007) concluded that RNF125 ubiquitination function serves as a negative regulatory route for IFN production.

Saito et al. (2007) found that RIGI and LGP2 (608588), but not MDA5, efficiently bound HCV RNA to confer IFNB expression. After HCV infection and RNA binding, RIGI shifted from a monomer to a self-associating protein that also interacted through its CARD domain with IPS1 (HISPPD2A; 610979) to signal IRF3- and NFKB-responsive genes. Mutation analysis showed that a RIGI C-terminal repressor domain (RD) was required for RIGI multimerization and IPS1 interaction. Deletion of the RD resulted in constitutive signaling to the IFNB promoter, whereas expression of the RD alone prevented signaling and increased cellular permissiveness to HCV. Saito et al. (2007) identified an analogous RD in LGP2 that interacted in trans with RIGI to ablate self-association and signaling. They concluded that RIGI is a pathogen recognition receptor for HCV and that its RD is a key modulator of host defenses controlling HCV infection and production. Saito et al. (2007) proposed that modulation of RIGI/LGP2 interaction dynamics may have therapeutic implications for immune regulation.

By RT-PCR, Western blot, and fluorescence microscopy analyses, Zhang et al. (2008) detected increased expression of RIGI in human and mouse myeloid leukemia cells upon retinoic acid-induced terminal granulocytic differentiation, suggesting that RIGI expression is developmentally regulated along with myeloid differentiation. Mice lacking Rigi developed progressive granulocytosis and chronic myeloid leukemia (see CML; 608232). The progressive granulopoiesis was associated with reduced expression of Icsbp1 (601565). Zhang et al. (2008) concluded that RIGI has a critical regulatory role in modulating the generation and differentiation of granulocytes.

RIGI is a cytosolic multidomain protein that detects viral RNA and elicits an antiviral immune response. Two N-terminal CARD domains transmit the signal, and the regulatory domain prevents signaling in the absence of viral RNA. Five-prime-triphosphate and dsRNA are 2 molecular patterns that enable RIGI to discriminate pathogenic from self-RNA. Using single-molecule protein-induced fluorescence enhancement, Myong et al. (2009) discovered a robust adenosine 5-prime triphosphate-powered dsRNA translocation activity of RIGI. The CARDs dramatically suppress translocation in the absence of 5-prime-triphosphate, and the activation by 5-prime-triphosphate triggers RIGI to translocate preferentially on dsRNA in cis. Myong et al. (2009) concluded that this functional integration of 2 RNA molecular patterns may provide a means to specifically sense and counteract replicating viruses.

Oshiumi et al. (2010) stated that RIPLET (RNF135; 611358) mediates lys63-linked polyubiquitination of the RIGI C-terminal repressor domain and N-terminal CARDs. They found that fibroblasts, macrophages, and dendritic cells from Riplet -/- mice were defective for production of IFN and other cytokines in response to infection with RNA viruses, but not DNA viruses. The lack of Riplet abolished Rigi activation during RNA virus infection, and Riplet -/- mice were more susceptible to vesicular stomatitis virus infection. Oshiumi et al. (2010) concluded that RIPLET is essential for regulating the RIGI-mediated innate immune response against RNA virus infection in vivo.

Kok et al. (2011) noted that RIGI shares structural similarity with DICER (606241), an RNase III-type nuclease that mediates RNA interference and requires dsRNA-binding partners, such as PACT (PRKRA; 603424), for optimal activity. They showed that PACT physically bound to the C-terminal repression domain of RIGI and stimulated RIGI-induced type I IFN production. PACT potentiated RIGI activation by poly(I:C) and helped sustain antiviral responses. Kok et al. (2011) concluded that PACT has an important role in initiating and sustaining RIGI-dependent antiviral responses.

Goubau et al. (2014) showed that RIGI, encoded by DDX58, mediates antiviral responses to RNAs bearing 5-prime-diphosphates (5-prime-pp) as well as those bearing 5-prime-triphosphates (5-prime-ppp). Genomes from mammalian reoviruses with 5-prime-pp termini, 5-prime-pp RNA isolated from yeast L-A virus, and base-paired 5-prime-pp RNAs made by in vitro transcription or chemical synthesis all bind to RIGI and serve as RIGI agonists. Furthermore, a RIGI-dependent response to 5-prime-pp RNA is essential for controlling reovirus infection in cultured cells and in mice. Goubau et al. (2014) concluded that the minimal determinant for RIGI recognition is a base-paired RNA with 5-prime-pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5-prime-pp RNA, like that of 5-prime-ppp RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.

Mutations in TDP43 (TARDBP; 605078), including ala315-to-thr (A315T; 605078.0009), are a rare cause of amyotrophic lateral sclerosis (ALS10; 612069). However, pathology of TDP43, which encodes an RNA-binding ribonuclear protein involved in RNA processing, is common to over 95% of ALS cases. Transgenic Tdp43 A315T mice develop age-dependent motor neuron degeneration and serve as a model for ALS. Using translating ribosome affinity purification and microarray analysis, MacNair et al. (2016) found that several mRNAs were abnormally regulated in 10-month-old symptomatic Tdp43 A315T mice compared with wildtype controls and 5-month-old presymptomatic Tdp32 A315T mice. Among the misregulated mRNAs was Ddx58, which was upregulated over 2-fold in mutant mice. Immunohistochemical analysis showed abnormally elevated Ddx58 expression in cytoplasm of motor neurons in 10-month-old Tdp43 A315T mice. Expression of human DDX58 was also upregulated in motor neurons and surrounding glial cells in spinal cords of sporadic and familial ALS patients. RNA immunoprecipitation analysis showed that Ddx58 was a direct target of Tdp43 in transfected mouse neuroblastoma cells.


Biochemical Features

Crystal Structure

To understand the synergy between the helicase and the repressor domain for RNA binding, and the contribution of ATP hydrolysis to RIGI activation, Jiang et al. (2011) determined the structure of the human RIGI helicase repressor domain in complex with dsRNA and an ATP analog. The helicase repressor domain organizes into a ring around dsRNA, capping one end, while contacting both strands using previously uncharacterized motifs to recognize dsRNA. Small-angle x-ray scattering, limited proteolysis, and differential scanning fluorimetry indicated that RIGI is in an extended and flexible conformation that compacts upon binding RNA. These results provided a detailed view of the role of helicase in dsRNA recognition, the synergy between the repressor domain and the helicase for RNA binding, and the organization of full-length RIGI bound to dsRNA, and provided evidence of a conformational change upon RNA binding. The RIGI helicase repressor domain structure is consistent with dsRNA translocation without unwinding and cooperative binding to RNA. The structure yielded unprecedented insight into innate immunity and had a broader impact on other areas of biology, including RNA interference and DNA repair, which utilize homologous helicase domains with DICER (606241) and FANCM (609644).

Peisley et al. (2014) reported the crystal structure of the tetramer of human RIGI tandem caspase activation and recruitment domain (2CARD) bound by 3 chains of lys63-linked diubiquitin (K63-Ub2). 2CARD assembles into a helical tetramer resembling a 'lock-washer,' in which the tetrameric surface serves as a signaling platform for recruitment and activation of the downstream signaling molecule, MAVS (609676). Ubiquitin chains are bound along the outer rim of the helical trajectory, bridging adjacent subunits of 2CARD and stabilizing the 2CARD tetramer. The combination of structural and functional analyses revealed that binding avidity dictates the K63-linkage and chain-length specificity of 2CARD, and that covalent ubiquitin conjugation of 2CARD further stabilizes the Ub-2CARD interaction and thus the 2CARD tetramer.


Molecular Genetics

Singleton-Merten Syndrome 2

In a large 4-generation Korean family with glaucoma, aortic and valvular calcification, and skeletal anomalies (SGMRT2; 616298), Jang et al. (2015) identified heterozygosity for a missense mutation in the DDX58 gene (E373A; 609631.0001) that segregated with disease. Affected individuals in another Korean family with SGMRT2 who exhibited only glaucoma and skeletal anomalies were heterozygous for a different missense mutation in DDX58 (C268F; 609631.0002). Functional analysis revealed that both mutations confer constitutive activation and result in increased interferon activity and interferon-stimulated gene expression.

Associations Pending Confirmation

Because of the 2 to 10% primary failure rate of measles vaccination and the importance of innate immunity to prevent or reduce viral replication and spread until the adaptive immune response to eliminate the virus, Haralambieva et al. (2011) performed a comprehensive candidate gene association study in a racially diverse cohort of 745 healthy schoolchildren in Minnesota who had had 2 doses of measles vaccine. Variants within DDX58 were associated with measles-specific antibody variations in Caucasians. Four DDX58 polymorphisms in high linkage disequilibrium were also associated with variations in measles-specific IFNG and IL2 (147680) secretion in Caucasians. ADAR (146920) variants also had a role in regulating measles-specific IFNG responses in Caucasians. Two intronic OAS1 (164350) SNPs were associated with increased neutralizing antibody levels in African Americans. Haralambieva et al. (2011) concluded that multiple innate immunity genes and genetic variants are likely involved in modulating the adaptive immune response to live attenuated measles vaccine in Caucasians and African Americans.


Animal Model

Kato et al. (2005) generated Rigi-deficient mice and, using cells from these mice, found that Rigi, and not the TLR system, played an essential role in antiviral responses in fibroblasts and conventional dendritic cells (DCs). In contrast, antiviral responses in plasmacytoid DCs, which produce abundant IFNA (147660), used the TLR system, principally Tlr7 (300365) and Tlr9 (605474), rather than Rigi. The Rigi -/- mice rarely survived until birth, and histologic examination of embryonic day-12.5 mice showed massive liver degeneration. Survivors had retarded growth and died within 3 weeks after birth.

Using mice deficient in MDA5 (606951), Kato et al. (2006) showed that MDA5 and RIG1 recognize different types of double-stranded RNAs: MDA5 recognizes polyinosine-polycytidylic acid and RIG1 detects in vitro transcribed double-stranded RNAs. RNA viruses are also differentially recognized by RIG1 and MDA5. Kato et al. (2006) found that RIG1 is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus, and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, Rig1-null and Mda5-null mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Kato et al. (2006) concluded that, taken together, their data show that RIG1 and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.


ALLELIC VARIANTS 2 Selected Examples):

.0001   SINGLETON-MERTEN SYNDROME 2

RIGI, GLU373ALA
SNP: rs786204847, ClinVar: RCV000169760

In affected members of a large 4-generation Korean family with glaucoma, aortic and valvular calcification, and skeletal anomalies (SGMRT2; 616298), Jang et al. (2015) identified heterozygosity for a c.1118A-C transversion (c.1118A-C, NM_014314.3) in the DDX58 gene, resulting in a glu373-to-ala (E373A) substitution at a highly conserved residue within the Hel-1 core helicase domain. The mutation was not found in 500 Korean controls or in 13,006 chromosomes in the NHLBI Exome Variant Server database. Functional analysis in transfected HEK293FT cells demonstrated constitutive activation with the E383A mutant, resulting in increased interferon activity and interferon-stimulated gene expression. Human trabecular meshwork cells transduced with E383A showed cytopathic effects and a significant decrease in cell number compared to controls.


.0002   SINGLETON-MERTEN SYNDROME 2

RIGI, CYS268PHE
SNP: rs786204848, ClinVar: RCV000169761

In a 20-year-old Korean woman, her mother, and her maternal grandmother, who all had glaucoma and skeletal anomalies (SGMRT2; 616298), Jang et al. (2015) identified heterozygosity for a c.803G-T transversion (c.803G-T, NM_014314.3) in the DDX58 gene, resulting in a cys268-to-phe (C268F) substitution at a highly conserved residue within the Hel-1 core helicase domain. The mutation was not found in 500 Korean controls or in 13,006 chromosomes in the NHLBI Exome Variant Server database. Functional analysis in transfected HEK293FT cells demonstrated constitutive activation with the C268F mutant, resulting in increased interferon activity and interferon-stimulated gene expression. Human trabecular meshwork cells transduced with C268F showed cytopathic effects and a significant decrease in cell number compared to controls.


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Contributors:
Patricia A. Hartz - updated : 02/16/2016
Marla J. F. O'Neill - updated : 4/7/2015
Ada Hamosh - updated : 11/4/2014
Ada Hamosh - updated : 5/29/2014
Matthew B. Gross - updated : 7/20/2012
Paul J. Converse - updated : 7/3/2012
Paul J. Converse - updated : 3/1/2012
Ada Hamosh - updated : 1/3/2012
Paul J. Converse - updated : 4/23/2009
Ada Hamosh - updated : 3/17/2009
Paul J. Converse - updated : 8/23/2007
Paul J. Converse - updated : 6/19/2007
Ada Hamosh - updated : 5/29/2007
Ada Hamosh - updated : 1/10/2007
Ada Hamosh - updated : 6/1/2006

Creation Date:
Paul J. Converse : 10/5/2005

Edit History:
carol : 05/27/2025
mgross : 12/10/2024
mgross : 07/14/2020
mgross : 02/16/2016
carol : 4/7/2015
mcolton : 4/7/2015
alopez : 11/4/2014
alopez : 5/29/2014
mgross : 7/20/2012
mgross : 7/20/2012
terry : 7/3/2012
mgross : 5/8/2012
terry : 3/1/2012
alopez : 1/6/2012
terry : 1/3/2012
mgross : 4/30/2009
terry : 4/23/2009
alopez : 3/23/2009
terry : 3/17/2009
mgross : 8/23/2007
mgross : 6/20/2007
mgross : 6/19/2007
alopez : 6/12/2007
terry : 5/29/2007
alopez : 1/11/2007
terry : 1/10/2007
alopez : 6/3/2006
terry : 6/1/2006
mgross : 10/5/2005
mgross : 10/5/2005
mgross : 10/5/2005



NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.
Printed: June 19, 2025