Loss-of-function mutations E6 27X and I923V of IFIH1 are associated with lower poly(I:C)–induced interferon-β production in peripheral blood mononuclear cells of type 1 diabetes patients

Chistiakov, Dimitry A.; Voronova, Natalia V.; Savost’anov, Kirill V.; Туракулов, Р. И.

doi:10.1016/j.humimm.2010.08.005

Cited by 35 publications

(38 citation statements)

References 50 publications

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“…Further evidence for a loss of function phenotype of E627X was shown by measuring polyI:C-induced IFNβ expression from donor PBMCs stratified according to MDA5 haplotype. E627X heterozygotes displayed reduced IFNβ production relative to the wild-type (WT) homozygotes [62]. This is in line with the evidence showing a lack of E627X expression, as absence of functional MDA5 will prevent downstream signaling to IFNβ.…”

Section: T1d-associated Rare Snpssupporting

confidence: 83%

“…Two of these SNPs (rs35667974 and rs35744605) were later confirmed in a Russian cohort [62]. These rare alleles are associated with protection from T1D in contrast to the common SNP rs1990760 which shows an association with risk for T1D.…”

Section: T1d-associated Rare Snpsmentioning

confidence: 88%

“…Comparison of the T1D/ control populations with the same haplotype revealed no significant difference in total IFNβ produced within the first 15 h following polyI:C treatment. Interestingly, 36 h after treatment, the T1D population had significantly higher IFNβ expression relative to controls with the same haplotype and the trend was greatest amongst the WT haplotype (2-fold WT T1D vs. Cont and 1.5-fold E627X T1D vs. Cont) [62]. This suggests that the IFN-I response involves a complex interaction between IFIH1 polymorphisms and other T1D-associated genetic loci.…”

Section: T1d-associated Rare Snpsmentioning

confidence: 94%

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Effects of Type 1 Diabetes-Associated IFIH1 Polymorphisms on MDA5 Function and Expression

et al. 2015

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Recent evidence has highlighted the role of the innate immune system in type 1 diabetes (T1D) pathogenesis. Specifically, aberrant activation of the interferon response prior to seroconversion of T1D-associated autoantibodies supports a role for the interferon response as a precipitating event toward activation of autoimmunity. Melanoma differentiation-associated protein 5 (MDA5), encoded by IFIH1, mediates the innate immune system's interferon response to certain viral species that form double-stranded RNA (dsRNA), the MDA5 ligand, during their life cycle. Extensive research has associated single nucleotide polymorphisms (SNPs) within the coding region of IFIH1 with T1D. This review discusses the different risk and protective IFIH1 alleles in the context of recent structural and functional analysis that relate to MDA5 regulation of interferon responses. These studies have provided a functional hypothesis for IFIH1 T1D-associated SNPs' effects on MDA5-mediated interferon responses as well as supporting the genome-wide association (GWA) studies that first associated IFIH1 with T1D.

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Section: T1d-associated Rare Snpssupporting

confidence: 83%

Section: T1d-associated Rare Snpsmentioning

confidence: 88%

Section: T1d-associated Rare Snpsmentioning

confidence: 94%

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Effects of Type 1 Diabetes-Associated IFIH1 Polymorphisms on MDA5 Function and Expression

et al. 2015

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“…Third, given that filament formation is inhibited by the ATPase activity of MDA5 (8), and that ATPase-deficient mutants of MDA5 exhibit constitutive signaling in cells (18), filaments-or filamentlike structures-may be involved in signaling. Similarly, a natural partial loss-of-function mutant in the MDA5 CTD (I923V) reduces binding cooperativity and filament formation in vitro (9) while reducing signaling in vivo (19,20), supporting a physiological role for filaments in signaling. The discovery that MDA5 polymerizes into helical filaments along dsRNA supports a signal transduction mechanism in which the helical array of MDA5 CARDs on the outside of MDA5-RNA filaments recruits MAVS and nucleates its assembly into an active fibril form.…”

Section: Resultsmentioning

confidence: 91%

MDA5 assembles into a polar helical filament on dsRNA

Berke

Xiong

Modis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

106

104

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Melanoma differentiation-associated protein 5 (MDA5) detects viral dsRNA in the cytoplasm. On binding of RNA, MDA5 forms polymers, which trigger assembly of the signaling adaptor mitochondrial antiviral-signaling protein (MAVS) into its active fibril form. The molecular mechanism of MDA5 signaling is not well understood, however. Here we show that MDA5 forms helical filaments on dsRNA and report the 3D structure of the filaments using electron microscopy (EM) and image reconstruction. MDA5 assembles into a polar, singlestart helix around the RNA. Fitting of an MDA5 homology model into the structure suggests a key role for the MDA5 C-terminal domain in cooperative filament assembly. Our study supports a signal transduction mechanism in which the helical array of MDA5 within filaments nucleates the assembly of MAVS fibrils. We conclude that MDA5 is a polymerization-dependent signaling platform that uses the amyloid-like self-propagating properties of MAVS to amplify signaling.innate immune receptor | ligand-binding cooperativity | nucleic acid sensor | prion-like switch | DExD/H-box RNA helicase

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“…(Fig. 5A), which has been associated with a reduced risk for type 1 diabetes, was reported to have reduced signaling activity but retain similar affinity to a dsRNA mimic, poly I∶C, as WT MDA5 (23,24). We asked whether the reduced signaling by I923V is due to impaired filament assembly and stability.…”

Section: Mda5mentioning

confidence: 99%

Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition

Peisley

Lin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

260

312

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MDA5, an RIG-I-like helicase, is a conserved cytoplasmic viral RNA sensor, which recognizes dsRNA from a wide-range of viruses in a length-dependent manner. It has been proposed that MDA5 forms higher-order structures upon viral dsRNA recognition or during antiviral signaling, however the organization and nature of this proposed oligomeric state is unknown. We report here that MDA5 cooperatively assembles into a filamentous oligomer composed of a repeating segmental arrangement of MDA5 dimers along the length of dsRNA. Binding of MDA5 to dsRNA stimulates its ATP hydrolysis activity with little coordination between neighboring molecules within a filament. Individual ATP hydrolysis in turn renders an intrinsic kinetic instability to the MDA5 filament, triggering dissociation of MDA5 from dsRNA at a rate inversely proportional to the filament length. These results suggest a previously unrecognized role of ATP hydrolysis in control of filament assembly and disassembly processes, thereby autoregulating the interaction of MDA5 with dsRNA, and provides a potential basis for dsRNA length-dependent antiviral signaling. (1). Upon viral RNA recognition, RIG-I and MDA5 interact with a common signaling adaptor, MAVS and activate NF-kB and IRF3/7 signaling pathways, resulting in the expression of type I interferon and proinflammatory cytokines (2).Previous studies suggested that RIG-I and MDA5 recognize largely distinct groups of viruses through their divergent RNA specificity (3, 4). RIG-I detects a variety of positive and negative strand viruses through recognition of a 5′ triphosphate group and blunt ends of genomic RNAs (3, 5, 6). By contrast, MDA5 detects several positive strand and dsRNA viruses such as picornaviruses and reoviruses through recognition of dsRNA replication intermediates and genomic dsRNAs (3,4,7). This viral RNA recognition by MDA5 is independent of 5′ triphosphate or blunt end, but instead depends on dsRNA length in a range of approximately 1-7 kb (8).The precise mechanism for length-dependent dsRNA recognition by MDA5 is poorly understood. Previous studies suggest that ATP hydrolysis could play an important role in both interferon signaling and RNA specificity (1, 2). The current model of MDA5 (or RIG-I) mediated signal activation is that binding of viral RNA to MDA5 triggers ATP hydrolysis in the conserved helicase domain, which then alters the receptor conformations or accessibility of the signaling domain (a tandem caspase activation recruitment domain) to allow its interaction with MAVS (1, 9). The proposed role of ATP hydrolysis as a conformational switch for signaling is supported by the requirement of ATP in the reconstituted signaling system of RIG-I (9, 10) and the observation that mutations in the active site for ATP hydrolysis either constitutively activate or inactivate interferon signaling by 12). In addition, induction of ATP hydrolysis by dsRNA has been shown to correlate with stimulation of interferon signaling (6, 13).It has been proposed that MDA5 (and RIG-I) forms a higher-order st...

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Loss-of-function mutations E6 27X and I923V of IFIH1 are associated with lower poly(I:C)–induced interferon-β production in peripheral blood mononuclear cells of type 1 diabetes patients

Cited by 35 publications

References 50 publications

Effects of Type 1 Diabetes-Associated IFIH1 Polymorphisms on MDA5 Function and Expression

Effects of Type 1 Diabetes-Associated IFIH1 Polymorphisms on MDA5 Function and Expression

MDA5 assembles into a polar helical filament on dsRNA

Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition

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