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FLASH GENE

Symbol

DDX58

contributors: mct/pgu - updated : 12-10-2017

HGNC name	DEAD (Asp-Glu-Ala-Asp) box polypeptide 58
HGNC id	19102

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	SGMS1 Singleton- Merten syndrome 1
Location	9p21.1      Physical location : 32.455.300 - 32.526.322
Synonym name	retinoic acid-inducible gene-I
	RNA helicase RIG-I
Synonym symbol(s)	RIG-I, FLJ13599, DKFZp434J1111, RIG-1, SGMRT2, RLR1
EC.number	3.6.1.-

DNA

TYPE	functioning gene
STRUCTURE	71.02 kb     18 Exon(s)

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_014314 18 - 4759 NP_055129 - 925 - 2004 15208624

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular vessel       moderately Digestive esophagus       predominantly   intestine small intestine     highly   mouth tongue     highly Reproductive female system breast mammary gland   highly Respiratory respiratory tract trachea     highly Urinary bladder       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow       Muscular       moderately

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune dendritic cell Homo sapiens Lymphoid/Immune macrophage Homo sapiens not specific fibroblast Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal caspase recruitment domains (CARDs)undergoing robust ubiquitination induced by TRIM25 in mammalian cells (AAs 1-190)
	two CARD domains responsible for interaction with and signaling through MAVS
	an helicase ATP binding domain responsible for dsRNA recognition
	DEAD/DEAH (Asp-Glu-Ala-Asp/His) box domain
	a zinc-binding domain structurally related to GDP/GTP exchange factors of Rab-like GTPases, essential for its signaling
	a repressor domain (RD), initially identified as AAs 735–925, is responsible for diminished basal activity, 55 AAs linker between the helicase domain and CTD
	an helicase C-terminal domain, regulatory domain (RD) binding viral RNA in a 5 prime-triphosphate-dependent manner and activating the DDX58 ATPase by RNA-dependent dimerization , and responsible for RNA binding (AAs 802–925)

conjugated

ubiquitinated , Other

mono polymer

monomer

HOMOLOGY

interspecies

homolog to murine Ddx58 (76.8 pc)

intraspecies

homolog to IFIH1

Homologene

FAMILY	RIG-I-like receptor (RLR) family
	DExH box family protein

CATEGORY

enzyme , regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm

basic FUNCTION	acting as an RNA helicase
	involved in innate immune defense against viruses
	triggering a transduction cascade involving MAVS, which results in the activation of NF-kappa-B, IRF3 and IRF7 and the induction of the expression of antiviral cytokines such as IFN-beta and RANTES (CCL5)
	may play a key role in interferon-based therapies for the treatment of HCV infection
	efficiently binds to secondary structured HCV RNA to confer induction of IFN-beta expression
	being essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza viruses and Japanese encephalitis virus
	essential intracellular sensor for several viruses and elicits antiviral interferon (IFN) responses by recognizing viral double-stranded RNAs (dsRNAs)
	acting as a mediator of the cytokine network in the inflammatory skin diseases, such as psoriasis vulgaris
	cytosolic viral RNA receptor that interacts with MAVS to induce type I interferon-mediated host protective innate immunity against viral infection
	initiates a signaling cascade that activates innate immune response by interferon and cytokine production, providing essential antiviral protection for the host
	cytosolic pattern recognition receptors detecting single-stranded or double-stranded RNA in virally infected cells
	recognize single-stranded RNA with 5prime triphosphates and double-stranded RNA (dsRNA) to initiate innate antiviral immune responses
	cytoplasmic DEX(D/H) helicase protein that can induce signaling in response to RNA ligands, including those from viral infections
	DDX58 signalling mediates the expression of two important mediators of inflammation, IL6 and IL8
	activation of DDX58 leads to endothelial dysfunction, and DDX58-induced endothelial damage could therefore be an important pathway in atherogenesis
	DDX58 and IFIH1 have emerged as key cytosolic sensors for the detection of RNA viruses and lead to antiviral interferon (IFN) production
	IFIH1 and DDX58 sense viral RNA in the cytoplasm of infected cells and activate signal transduction pathways that trigger the production of type I interferons (IFNs)
	DDX58 -mediated antiviral signaling serves as the first line of defense against viral infection
	interacts with DDX58 and MAVS
	plays important roles in pathogen recognition and antiviral signalling transduction

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

immunity/defense

text	antiviral defense

PATHWAY

metabolism

signaling

a component	isgylated (conjugated to ubiquitin-like protein ISG15 upon IFN-beta stimulation)
	WRNIP1-TRIM14-PPP6C mitochondrial signalosome required for DDX58-mediated innate antiviral immunity

INTERACTION

DNA

RNA	binding to dsRNA produced during viral replication
	while DDX58 binds to a dsRNA end as a monomer in the absence of ATP, it assembles in the presence of ATP into a filament that propagates from the dsRNA end to the interior

small molecule	nucleotide,
	ATP

protein	interacting with MAVS/IPS1
	interacting with DHX58/LGP2, with IKBKE and TBK1
	RNF135 interacting with DDX58
	interacting with DHX58 (facilitates viral RNA recognition by DDX58 and IFIH1 through its ATPase domain
	ZC3HAV1 is a key regulator of DDX58 signaling during the innate antiviral immune response
	TRIM25 interaction with DDX58
	KL interacts with DDX58 and this interaction inhibits DDX58-induced expression of IL6 and IL8
	PRKRA is an important component in initiating and sustaining the DDX58-dependent antiviral response
	PRKRIR is a DDX58 interacting protein (interacts through the C-terminal domain of PRKRIR, and the N-terminal region of PRKRIR potentially possesses inhibitory functions to block DDX58 interaction)
	ANKRD17 interacts with DDX58, IFIH1, and MAVS and upregulates RLR-mediated immune signaling
	TLR3 and DDX58 activation leads to a release of proinflammatory cytokines, which enhance atherosclerotic processes and affect other cell types
	TSPAN6 functions as a negative regulator of the DDX58 pathway by interacting with MAVS in a ubiquitination-dependent manner
	MUL1 is a novel regulator of the DDX58-like receptor-dependent antiviral response, that otherwise functions to limit inflammation
	RAD23A inhibits DDX58/IFIH1 signaling by interacting with TRAF2 and down-regulates its protein level (PMUID: 23357418)
	PPP1CA and PPP1CC are the primary phosphatases that are responsible for IFIH1 and DDX58 dephosphorylation
	that lead to their activation
	TRIM11 inhibits DDX58-mediated IFNB1 production by targeting the TBK1 signaling complex
	TFG plays likely a pivotal role in negative regulation of RNA-sensing, DDX58 family signaling pathways
	RNF135 was dispensable for DDX58 RNA binding activity but required for TRIM25 to activate DDX58
	forms signaling-competent filaments in an ATP-dependent, ubiquitin-independent manner
	MEX3C is an E3 ubiquitin ligase that modifies DDX58 in stress granules and plays a critical role in eliciting antiviral immune responses
	MAVS and TMEM173 transduce signals from the cytosolic nucleic acid sensors DDX58 and CGAS, respectively
	exerts its antiviral activity mainly through governing its downstream regulators DDX58 and IFIH1 by gene splicing to activate IRF3 and induce classical ISG expression independent of the JAT-STAT signaling pathway
	during DDX58 activation induced by viral RNA, cytosolic FGF2 bound to the caspase recruitment domains of activated DDX58, which blocked DDX58-MAVS complex formation
	UBD is a novel negative regulator of DDX58-mediated inflammatory response
	SDC4 interacts with both DDX58 and deubiquitinase CYLD via its C-terminal intracellular region, and likely promotes redistribution of DDX58 and CYLD in a perinuclear pattern post viral infection
	SRP54 interacted with both DDX58 and IFIH1 and impaired their association with MAVS
	RNF135 play a central role in the activation of the retinoic acid-inducible gene I (DDX58), and is a novel ZAP cofactor

cell & other

REGULATION

induced by	bacterial lipopolysaccharide (LPS) in endothelial cells
		IFN-alpha
		IFN-beta
		IFN-gamma
		induced through the ataxia telangiectasia mutated-interferon regulatory factor 1 (ATM-IRF1) axis in senescent cells (
		senescence associated DNA damage resulting in release of proinflammatory cytokines IL6/8

Other	ubiquitinated by RNF125, an ubiquitin E3 ligase, leading to proteasomal degradation
	its repression in uninfected cells is crucial for tight regulation of the host immune system and prevents unwanted production of IFN under ordinary conditions

ASSOCIATED DISORDERS

corresponding disease(s)

SGMS1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   most lung cells from stable Chronic Obstructive Pulmonary Disease (COPD) patients show a constitutive decreased expression of IFNB1, IRF7, DDX58 and IFIH1, suggesting that this deficiency is the main cause of their acute viral exacerbations

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cardiovascular atheroma   specific DDX58 activation greatly impairs endothelial function and could therefore become a target in the search for direct atherosclerotic treatment options

ANIMAL & CELL MODELS