DDX58

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases which are implicated in a number of cellular processes involving RNA binding and alteration of RNA secondary structure. This gene encodes a protein containing RNA helicase-DEAD box protein motifs and a caspase recruitment domain (CARD). It is involved in viral double-stranded (ds) RNA recognition and the regulation of immune response. [provided by RefSeq, Jul 2008]

DDX58

Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and proinflammatory cytokines. Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments. The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms (PubMed:28469175, PubMed:31006531).

Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons (PubMed:28469175, PubMed:31006531).

Ligands include 5'-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (<1 kb in length). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential. Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity. A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity. Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV). It also detects rotaviruses and reoviruses. Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration.

Antiviral innate immune response Source: UniProtKB
Cellular response to exogenous dsRNA Source: UniProtKB
Cytoplasmic pattern recognition receptor signaling pathway in response to virus Source: UniProtKB
Defense response to virus Source: UniProtKB
Detection of virus Source: BHF-UCL
Innate immune response Source: UniProtKB
Negative regulation of type I interferon production Source: Reactome
Positive regulation of defense response to virus by host Source: UniProtKB
Positive regulation of DNA-binding transcription factor activity Source: BHF-UCL
Positive regulation of gene expression Source: CACAO
Positive regulation of granulocyte macrophage colony-stimulating factor production Source: CACAO
Positive regulation of interferon-alpha production Source: UniProtKB
Positive regulation of interferon-beta production Source: BHF-UCL
Positive regulation of interleukin-6 production Source: CACAO
Positive regulation of interleukin-8 production Source: CACAO
Positive regulation of myeloid dendritic cell cytokine production Source: UniProtKB
Positive regulation of response to cytokine stimulus Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: BHF-UCL
Positive regulation of tumor necrosis factor production Source: UniProtKB
Protein deubiquitination Source: Reactome
Regulation of cell migration Source: UniProtKB
Regulation of type III interferon production Source: UniProtKB
Response to exogenous dsRNA Source: UniProtKB
response to virus Source: GO_Central
RIG-I signaling pathway Source: UniProtKB
Viral process Source: UniProtKB-KW

Ruffle membrane; Cytoplasm; Cytoskeleton; Tight junction. Colocalized with TRIM25 at cytoplasmic perinuclear bodies. Associated with the actin cytoskeleton at membrane ruffles.

Singleton-Merten syndrome 2 (SGMRT2):
A form of Singleton-Merten syndrome, an autosomal dominant disorder characterized by marked aortic calcification, dental anomalies, osteopenia, acro-osteolysis, and to a lesser extent glaucoma, psoriasis, muscle weakness, and joint laxity. Additional clinical manifestations include particular facial characteristics and abnormal joint and muscle ligaments. SGMRT2 is an atypical form characterized by variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies.

(Microbial infection) Deamidated on 'Asn-495' and 'Asn-549' by herpes simplex virus 1 protein UL37. These modifications eliminate DDX58 detection of viral RNA and restriction of viral replication.
(Microbial infection) Cleaved by the protease 3C of coxsackievirus B3, poliovirus and enterovirus 71 allowing the virus to disrupt the host type I interferon production.
Phosphorylated in resting cells and dephosphorylated in RNA virus-infected cells. Phosphorylation at Thr-770, Ser-854 and Ser-855 results in inhibition of its activity while dephosphorylation at these sites results in its activation.
ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN-beta stimulation. ISGylation negatively regulates its function in antiviral signaling response.
Sumoylated, probably by MUL1; inhibiting its polyubiquitination.
Ubiquitinated. 'Lys-63' ubiquitination by RNF135, which occurs after RNA-binding and homodimerization, releases the autoinhibition of the CARD domains by the RLR CTR domain, an essential step in the activation of the RIG-I signaling pathway (PubMed:23950712, PubMed:28469175, PubMed:31006531). Lys-172 is the critical site of ubiquitination for MAVS/IPS1 binding and to induce anti-viral signal transduction (PubMed:17392790, PubMed:30193849). Lys-154, Lys-164 and Lys-172 are shared sites for RNF135-mediated and TRIM4-mediated ubiquitination (PubMed:19017631, PubMed:19484123, PubMed:24755855). Also undergoes 'Lys-48' ubiquitination at Lys-181 by RNF125 that leads to proteasomal degradation (PubMed:17460044, PubMed:26471729). 'Lys-48' ubiquitination follows viral infection and is enhanced by 'Lys-63'-linked ubiquitination of the CARD domains that promotes interaction with VCP/p97 and subsequent recruitment of RNF125 (PubMed:17460044, PubMed:26471729). Within a negative feedback loop involving SIGLEC10 and PTPN11, 'Lys-48' ubiquitination at Lys-812 by CBL also elicits the proteasomal degradation of DDX58 (By similarity). Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains (PubMed:18636086). Also probably deubiquitinated by USP17L2/USP17 that cleaves 'Lys-48'- and 'Lys-63'-linked ubiquitin chains and positively regulates the receptor (PubMed:20368735). Ubiquitinated by TRIM40 via 'Lys-48'-linked ubiquitination; leading to proteasomal degradation (PubMed:29117565).