Structural basis of double-stranded RNA recognition by the RIG-I like receptor MDA5

Li, Xiaojun; Lü, Cheng; Stewart, Mark; Xu, Hengyu; Strong, Roland K.; Igumenova, Tatyana I.; Li, Pingwei

doi:10.1016/j.abb.2009.06.008

Cited by 96 publications

(111 citation statements)

References 37 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…To identify the remaining MDA5 domains in the EM density, we fitted a homology model of ΔCARD-MDA5 based on the structures of MDA5 fragments (8,10) and of RIG-I bound to A-form RNA and nucleotide (5) into the density. The reconstruction had an enantiomorphic ambiguity, because both the volume shown and its mirror image were equally consistent with the observed projections.…”

Section: Resultsmentioning

confidence: 99%

“…A homology model of mouse ΔCARD-MDA5 (304-1026) was generated with MODELER v9.10 (28) using the crystal structures of human MDA5 Hel1 [Protein Data Bank (PDB) ID code 3B6E], mouse MDA5 Hel2i (PDB ID code 3TS9) (8), human MDA5 CTD (PDB ID code 3GA3) (10), and RIG-I bound to ADP-BeF 3 and a 14-bp dsRNA (PDB ID code 3TMI) as templates (5). In the MDA5 CTD crystal structure, a motif at the C terminus conserved across species in MDA5 but absent in RIG-I (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, MDA5 does not sequester its CARDs (8) and cooperatively assembles into ATP-sensitive filaments on dsRNA (8,9). Moreover, the MDA5 CTD is required for cooperative filament assembly, but not for RNA binding (8,10,11). The MDA5 CARDs have been proposed to nucleate the assembly of MAVS into its active fibril form (8,12) in a process involving free polyubiquitin chains (13).…”

mentioning

confidence: 99%

See 2 more Smart Citations

MDA5 assembles into a polar helical filament on dsRNA

Berke

Xiong

Modis

et al. 2012

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

108

104

View full text Add to dashboard Cite

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

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

MDA5 assembles into a polar helical filament on dsRNA

Berke

Xiong

Modis

et al. 2012

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

108

104

View full text Add to dashboard Cite

show abstract

“…1). It activates cells from the endosome, through TLR3-initiated TRIF signaling, and from the cytosol through the helicase MDA-5 (22,24). Because the induction of cytokines by poly-IC is known to be facilitated by CD14 (49), we stimulated the BMMCs with poly-IC in the presence and absence of sCD14 and determined the TNF-a, IL-6, and IFN-ab response.…”

Section: Absence Of Ifn-ab Response To Dsrna Recombinant Human Adenomentioning

confidence: 99%

“…It is therefore not surprising that mast cells, in contrast to macrophages, do not produce IFN-b in response to LPS and moreover that IL-6 or TNF-a responses in LPS-treated mast cells from wild type (WT) and TRIF-deficient mice are comparable. In addition, we show that mast cells do not express IFN-ab in response to IFN inducers, such as dsRNA (22)(23)(24), B-DNA (25), and adenovirus (26), which use distinct, TLR4-independent endosomal or cytosolic receptors.…”

mentioning

confidence: 99%

Absence of TRIF Signaling in Lipopolysaccharide-Stimulated Murine Mast Cells

Keck

Müller

Fejér

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

In macrophages, two signaling pathways, dependent on MyD88 or TIR domain-containing adaptor-inducing IFN-β (TRIF) signaling, emanate from the LPS receptor TLR4/MD-2. In this study, we show that in murine bone marrow-derived mast cells (BMMCs), only the MyD88-dependent pathway is activated by LPS. The TRIF signaling branch leading both to NF-κB activation and enhanced proinflammatory cytokine production, as well as to IRF3 activation and subsequent IFN-β production, is absent in LPS-stimulated BMMCs. IRF3 activation is also absent in peritoneal mast cells from LPS-injected mice. We observed strongly diminished TRAM expression in BMMCs, but overexpression of TRAM only moderately enhanced IL-6 and did not boost IFN-β responses to LPS in these cells. A combination of very low levels of TRAM and TLR4/MD-2 with the known absence of membrane-bound CD14 are expected to contribute to the defective TRIF signaling in mast cells. We also show that, unlike in macrophages, in BMMCs the TRIF-dependent and -independent IFN-αβ responses to other recognized IFN inducers (dsRNA, adenovirus, and B-DNA) are absent. These results show how the response to the same microbial ligand using the same receptor can be regulated in different cell types of the innate immune system.

show abstract

Survey of the 2009 commercial optical biosensor literature

Rich

Myszka

2011

J of Molecular Recognition

View full text Add to dashboard Cite

We took a different approach to reviewing the commercial biosensor literature this year by inviting 22 biosensor users to serve as a review committee. They set the criteria for what to expect in a publication and ultimately decided to use a pass/fail system for selecting which papers to include in this year's reference list. Of the 1514 publications in 2009 that reported using commercially available optical biosensor technology, only 20% passed their cutoff. The most common criticism the reviewers had with the literature was that "the biosensor experiments could have been done better." They selected 10 papers to highlight good experimental technique, data presentation, and unique applications of the technology. This communal review process was educational for everyone involved and one we will not soon forget.

show abstract

Structural basis of double-stranded RNA recognition by the RIG-I like receptor MDA5

Cited by 96 publications

References 37 publications

MDA5 assembles into a polar helical filament on dsRNA

MDA5 assembles into a polar helical filament on dsRNA

Absence of TRIF Signaling in Lipopolysaccharide-Stimulated Murine Mast Cells

Survey of the 2009 commercial optical biosensor literature

Contact Info

Product

Resources

About