MDA5 assembles into a polar helical filament on dsRNA

Berke, Ian C.; Xiong, Yong; Modis, Yorgo; Egelman, Edward H.

doi:10.1073/pnas.1212186109

Cited by 106 publications

(108 citation statements)

References 31 publications

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Section: Unlike Rig-i Mda5 Binds Cooperatively To Long Rna Duplexmentioning

confidence: 97%

“…47 Interestingly, although the data were obtained for both full-length and CARD-less MDA5, the authors could not locate the CARDs. 47 It is likely that in the activated MDA5:RNA complex, the CARDs do not form a stable interaction with the HEL-CTD domains, but are physically tethered to the HEL-CTD:RNA complex through the 100 amino acid-long non-structured linker between CARD2 and the HEL-CTD domains. The Hur group suggested that at least six to eight copies of the activated MDA5 (on a long duplex RNA of more than a hundred base pairs) form the minimal activation unit-comprising a multimeric head-to-tail filament with the free CARDs able to cluster together (Fig.…”

Section: Unlike Rig-i Mda5 Binds Cooperatively To Long Rna Duplexmentioning

confidence: 97%

Section: Unlike Rig-i Mda5 Binds Cooperatively To Long Rna Duplexmentioning

confidence: 99%

“…[46][47][48][49][50] This cooperativity is independent of the CARDs and the interface has been mapped to HEL1 of one molecule of MDA5 and the CTD of the neighboring molecule. 47,50 This cooperativity is necessary for activation of MDA5, as MDA5 displays poor cellular activity on short RNA species. 40,45,46 The structure of MDA5 lacking the CARDs in complex with a 12mer RNA duplex exhibits several differences from those of similar RIG-I:RNA complexes: first, the MDA5 CTD in the structure binds only to the backbone of the RNA duplex but not to the end (Fig.…”

Section: Unlike Rig-i Mda5 Binds Cooperatively To Long Rna Duplexmentioning

confidence: 99%

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Toward a crystal-clear view of the viral RNA sensing and response by RIG-I-like receptors

Luo

2014

RNA Biology

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Section: Unlike Rig-i Mda5 Binds Cooperatively To Long Rna Duplexmentioning

confidence: 97%

Section: Unlike Rig-i Mda5 Binds Cooperatively To Long Rna Duplexmentioning

confidence: 97%

Section: Unlike Rig-i Mda5 Binds Cooperatively To Long Rna Duplexmentioning

confidence: 99%

Section: Unlike Rig-i Mda5 Binds Cooperatively To Long Rna Duplexmentioning

confidence: 99%

See 2 more Smart Citations

Toward a crystal-clear view of the viral RNA sensing and response by RIG-I-like receptors

Luo

2014

RNA Biology

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“…Conventionally, assembling filaments on foreign nucleic acids has been considered as a defense strategy reserved for sensing intracellular RNA (28,42). For example, a principal mechanism by which melanoma differentiation associated protein (MDA)5 distinguishes self-from nonself-RNA is via cooperatively assembling into filaments along the length of long dsRNA with its two CARDs forming clusters tracing the center of filaments in a helical trajectory (25,26,(42)(43)(44)(45). IFI16 and MDA5 are unrelated proteins, and, not surprisingly, mechanisms allowing these proteins to assemble into filaments are significantly different.…”

Section: Discussionmentioning

confidence: 99%

Cooperative assembly of IFI16 filaments on dsDNA provides insights into host defense strategy

Morrone

Wang²,

Constantoulakis³

et al. 2013

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

148

208

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Whether host DNA receptors have any capacity to distinguish self from nonself at the molecular level is an outstanding question in the innate immunity of mammals. Here, by using quantitative assays and electron microscopy, we show that cooperatively assembling into filaments on dsDNA may serve as an integral mechanism by which human IFN-inducible protein-16 (IFI16) engages foreign DNA. IFI16 is essential for defense against a number of different pathogens, and its aberrant activity is also implicated in several autoimmune disorders, such as Sjögren syndrome. IFI16 cooperatively binds dsDNA in a length-dependent manner and clusters into distinct protein filaments even in the presence of excess dsDNA. Consequently, the assembled IFI16·dsDNA oligomers are clearly different from the conventional noninteracting entities resembling beads on a string. The isolated DNA-binding domains of IFI16 engage dsDNA without forming filaments and with weak affinity, and it is the non-DNA-binding pyrin domain of IFI16 that drives the cooperative filament assembly. The surface residues on the pyrin domain that mediate the cooperative DNA binding are conserved, suggesting that related receptors use a common mechanism. These results suggest that IFI16 clusters into signaling foci in a switch-like manner and that it is capable of using the size of naked dsDNA as a molecular ruler to distinguish self from nonself.cooperative filament formation | inflammasome R ecognition of foreign intracellular DNA is a widely conserved defense mechanism by which the innate immune system of mammals detects and responds to invading pathogens (1, 2). Using such a universal molecule as a major danger signal for detecting pathogens must be regulated in a stringent yet efficient manner. However, only a few deciding factors are known for the host innate immune system to selectively engage foreign DNA (i.e., nonself-DNA) while minimizing interactions with self-DNA, which include the compartmentalization of mammalian cells and the size of foreign DNA. These features, however, only raise more questions than provide answers. For example, the footprints of intracellular DNA receptors usually fall below 20 bp, and yet a long foreign DNA fragment [e.g., poly(dA:dT); ≥1,000 bp] is required to induce a robust innate immune response even in a normally DNA-free environment like the cytoplasm (1, 2). On the other hand, foreign DNA-sensing pathways also exist in the host nucleus in which DNA receptors must not respond to abundant self-DNA to prevent spurious activities (1, 2). Indeed, one of the major unresolved questions in understanding the DNA-sensing pathways of mammals is whether the host intracellular DNA receptors have any capacity to distinguish self-from nonself-DNA at the molecular level (2).Human IFN inducible protein-16 (IFI16) is an intracellular DNA receptor of innate immunity that belongs to the family of absent-in-melanoma-2 (AIM2)-like receptors (ALRs) (1-4). IFI16 senses DNA from invading pathogens in both the nucleus and cytoplasm [e.g., vaccinia virus...

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Structure‐guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG‐I

Yong

Zheng

et al. 2019

FEBS Letters

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The cytoplasmic immune sensor RIG‐I detects viral RNA and initiates an antiviral immune response upon activation. It has become a potential target for vaccination and immunotherapies. To develop the smallest but potent immunomodulatory RNA (immRNAs) species, we performed structure‐guided RNA design and used biochemical, structural, and cell‐based methods to select and characterize the immRNAs. We demonstrated that inserting guanosine at position 9 to the 10mer RNA hairpin (3p10LG9) activates RIG‐I more robustly than the parental RNA. 3p10LG9 interacts strongly with the RIG‐I helicase‐CTD RNA sensing module and disrupts the auto‐inhibitory interaction between the HEL2i and CARDs domains. We further showed that 3p10LA9 has a stronger cellular activity than 3p10LG9. Collectively, purine insertion at position 9 of the immRNA species triggered more robust activation of RIG‐1.

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MDA5 assembles into a polar helical filament on dsRNA

Cited by 106 publications

References 31 publications

Toward a crystal-clear view of the viral RNA sensing and response by RIG-I-like receptors

Toward a crystal-clear view of the viral RNA sensing and response by RIG-I-like receptors

Cooperative assembly of IFI16 filaments on dsDNA provides insights into host defense strategy

Structure‐guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG‐I

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