doi: 10.1038/nature13140.
Epub 2014 Mar 2.
Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I
Affiliations
- PMID: 24590070
- PMCID: PMC6136653
- DOI: 10.1038/nature13140
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Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I
Nature.
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Abstract
Ubiquitin (Ub) has important roles in a wide range of intracellular signalling pathways. In the conventional view, ubiquitin alters the signalling activity of the target protein through covalent modification, but accumulating evidence points to the emerging role of non-covalent interaction between ubiquitin and the target. In the innate immune signalling pathway of a viral RNA sensor, RIG-I, both covalent and non-covalent interactions with K63-linked ubiquitin chains (K63-Ubn) were shown to occur in its signalling domain, a tandem caspase activation and recruitment domain (hereafter referred to as 2CARD). Non-covalent binding of K63-Ubn to 2CARD induces its tetramer formation, a requirement for downstream signal activation. Here we report the crystal structure of the tetramer of human RIG-I 2CARD bound by three chains of K63-Ub2. 2CARD assembles into a helical tetramer resembling a 'lock-washer', in which the tetrameric surface serves as a signalling platform for recruitment and activation of the downstream signalling molecule, MAVS. Ubiquitin chains are bound along the outer rim of the helical trajectory, bridging adjacent subunits of 2CARD and stabilizing the 2CARD tetramer. The combination of structural and functional analyses reveals that binding avidity dictates the K63-linkage and chain-length specificity of 2CARD, and that covalent ubiquitin conjugation of 2CARD further stabilizes the Ub-2CARD interaction and thus the 2CARD tetramer. Our work provides unique insights into the novel types of ubiquitin-mediated signal-activation mechanism, and previously unexpected synergism between the covalent and non-covalent ubiquitin interaction modes.
Conflict of interest statement
The authors declare no competing financial interests.
Figures
a, IFN-β reporter activity of wild-type RIG-I and the K115A/R117A mutant with and without 42 bp dsRNA stimulation (mean ± s.d., n = 3). b, Left, EMSA analysis of tetramerization of wild-type and K115A/R117A RIG-I 2CARD (residues 1–200) with K63-Ubn (n > 8). 2CARD was N-terminally labelled with fluorescein using sortase (see Methods). Right, SDS analysis of wild-type and mutant 2CARD, and K63-Ubn chains used in this study. Unless mentioned otherwise, K63-Ubn indicates the chain length n > 8 throughout the manuscript, c, Mapping of K115 and R117 onto the crystal structure. Although K115 and R117 are located at the edge of the interface, K115A/R117A has little effect on the cellular signalling activity of RIG-I (a) and tetramerization of RIG-I 2CARD (b), indicating that these residues are not critical for mediating inter-domain contacts.
a, Simulated annealing omit maps (sigma-A weighted Fo-Fc, contoured at σ = 2.5). Four and six maps were separately calculated using models with individual second CARDs (left) and Ubs (middle and right) omitted, respectively, and were overlaid on the crystal structure. The omit maps for Ubs are shown from both the top (middle) and bottom (right) views for better visualization of both proximal and distal Ubs. Although the omit maps for Ub chains F, G, H and I are less well-defined than those for chains E and J, the overall density matches well with individual Ub structures, and thus supports our model. b, Two competing molecular replacement (MR) solutions for Ub chain I. During the early stage of molecular replacement, solutions Ib (grey) as well as Ia (red, final solution) received high Z-scores, but only Ia was confirmed once the rest of the complex (all four 2CARDs and Ub chains E–H and J) was fixed as a known solution (see Methods). In addition, the simulated annealing omit map from (a) matches Ia, not Ib. Based on these results, Ia was selected for our final model. c, B-factor representation of the 2CARD–Ub complex. Note that Ub chains F–I have high B-factors, indicative of a high degree of flexibility. See (d) for an explanation. d, Three types of crystallographic packing interactions. They are mediated by Ub(E)–Ub(J) contacts (left); 2CARD–Ub(E) and 2CARD–2CARD contacts (middle); and 2CARD–Ub(H) contacts (right). Solid lines indicate crystallographic contacts, whereas dotted lines indicate boundaries between adjacent 2CARD tetramers without direct contacts. Note that 2CARD–Ub(H) contacts are less intimate than other contacts. The extensive contacts with Ub(E) and Ub(J) explain lower B-factors observed with these two Ub chains in c. e, SDS–PAGE analysis of the crystals shows that K63-Ub2 in the crystal is intact. f, Analysis of distance between the C terminus and K63 of adjacent Ub chains. As residues 72–76 of several Ubs were disordered in the structure, we measured the distance between Cα of L71 (black sphere) and Cα of K63 (blue sphere). The distance requirement for covalent conjugation (<25Å) is shown on the right, assuming 3.5Å spacing per residue in the missing C-terminal tail, 2Å for the C-terminal carboxylate, 6Å for Lys side chains. This condition is only satisfied with three pairs of Ubs, which enabled us to unambiguously identify pairs of Ubs that are covalently connected through the K63-linkage. g, Two crystallographic packing arrangements, which can potentially allow sharing of a single chain of Ub2 by two neighbouring 2CARD tetramers. In these arrangements, K63 of Ub bound to one 2CARD tetramer is within the covalent conjugation distance (Cα distance <25Å) from L71 of Ub bound to a neighbouring 2CARD tetramer. Such Ub crossover would increase the heterogeneity in the Ub connectivity, and could have contributed to the poor electron density map corresponding to the K63-linker. The same colour code was used as in f.
a, Superposition of RIG-I 2CARD in the tetramer (subunits A–D) and 2CARD from full-length duck RIG-I (PDB: 4A2W). b, Superposition of full-length RIG-I (grey) onto the 2CARD tetramer by aligning 2CARD in full-length RIG-I with 2CARD subunit A (yellow) in the tetramer. The same colour code was used as in a. The superposition shows that the helicase domain in full-length RIG-I masks the 2CARD(A)–2CARD(B) interface and sterically blocks subunit B (green) from interacting with A. On the right, surface representation was separately shown for 2CARD(B) in the tetramer (top) and the helicase domain in full-length RIG-I (bottom) to further demonstrate the steric clash between the helicase domain and 2CARD(B). c, Geometric relationship between adjacent 2CARDs. Superposition of the ‘cut-out’ dimers of A–B, B–C and C–D (left), showing repetition of intermolecular interactions along the helical trajectory. The D–A interaction (middle) in the helical ‘seam’ (as defined in Fig. 1b) differs from the A–B, B–C and C–D interactions by a relative dislocation of A by a single CARD (right), d, IFN-β reporter activity of wild-type RIG-I and tetramer interface mutants (in Fig. 1d) with and without 42 bp dsRNA stimulation in 293T cells (mean ± s.d., n = 3).
Electron density map (2Fo-Fc) was contoured at σ = 0.9. A few residues at the interface were displayed as stick models with labels, a, Definition of the interaction surface type (same as in Fig. 1c). b, Intramolecular interaction between surface IIb and IIa of the first and second CARDs, respectively. c, Intermolecular interactions that repeat along the helical trajectory (A–B, B–C and C–D). Shown are the interactions between 2CARD(A) and (B), which are identical to those between (B) and (C), and between (C) and (D) (Extended Data Fig. 3c). These interactions involve three interfaces (shown in the left, middle and right panels). Each of these interfaces consists of a few (< 3–4) residues on each side of the molecules, suggesting that cooperativity of all three interactions might be important for the tetramer stability. The IIIa–IIIb interactions in the first and second CARDs (left and right panels) are more extensive than the Ia–Ib interaction (middle), and are in general electrostatic. Detailed interactions among the interface residues could not be unambiguously determined due to the limited resolution of the structure. d, Intermolecular interactions at the helical seam, which occurs only between 2CARD(D) and 2CARD(A). As with the interaction between 2CARD(A) and (B) (or between B and C, and between C and D along the helical trajectory), each of the three interfaces consists of a few (< 3–4) residues on each side of the molecules, and the IIIa–IIIb interaction is more extensive than either of the two Ia–Ib interactions. Note that IIIa of the second CARD interacts with IIIb of the first CARD at the helical seam, whereas it interacts with IIIb of the second CARD along the helical trajectory (c). This is despite the low level of conservation of IIIb between the first and second CARDs, and thus suggests plasticity in molecular interactions. Similarly, Ia of the second CARD also has two distinct interaction partners, that is, Ib of the second CARD at the helical seam and Ib of the first CARD along the helical trajectory (c). But in this case, Ia utilizes different residues (albeit in the same local area) to accommodate different interaction partners.
a, Superposition of RIG-I 2CARD in the tetramer (subunits A–D) bound with K63-Ub2. The three Ub2 chains bound to A–B, B–C and C–D–A were superposed by aligning chain A, B and C, respectively, b, Superposition of the first (dark grey) and second (light grey) CARDs from RIG-I 2CARD bound by proximal (red) or distal (salmon) Ubs. The good alignment suggests that the proximal Ub-binding site, IV, in the second CARD is equivalent to the distal Ub-binding site, VI, in the first CARD (see Fig. 3b for the definitions of IV and VI). c, Distance analysis between the C-terminal residue of the distal Ub and K63, K48 and M1 of the proximal Ub. The C-terminal tail (residues 74–76) of the distal Ub is disordered in the structure, and thus the distance was measured between Cα of residue 73 and Cα of the target Lys. Below is the distance requirement for covalent conjugation, assuming 3.5Å spacing per residue in the missing C-terminal tail, 2Å for the C-terminal carboxylate, 6Å for Lys side chains and 1.5Å for N-terminal amine. These distance requirements are satisfied only with K63, thus rationalizing the observed specificity of 2CARD for the K63-linkage. d, IFN-β reporter activity of full-length RIG-I stimulated with 21 bp, 42 bp and 112 bp dsRNAs or isolated 2CARD fused to GST (GST–2CARD) without RNA. Activities were compared between wild type and mutants defective in Ub binding (R71D/D75R and K95E/E98R) or conjugation (6KR), and were normalized against the wild-type values (mean ± s.d., n = 3). 6KR indicates Arg mutation of six Lys (K99, K169, K172, K181, K190 and K193) that are known to be conjugated with K63-Ubn. The signalling activity of full-length RIG-I with 21 bp dsRNA was completely abrogated by R71D/D75R, K95E/E98R or 6KR, suggesting the importance of both Ub-binding and conjugation. The negative impacts of K95E/E98R and 6KR were progressively alleviated by stimulation with increasing length of dsRNA (42 and 112 bp). This restoration of the signalling activity by longer dsRNAs is consistent with our previous report that filament formation of RIG-I on long dsRNA (>60 bp) promotes 2CARD tetramerization by the ‘proximity-induced’ mechanism. Note that 21 bp, 42 bp and 112 bp dsRNA can accommodate 1–2, 3, 8 RIG-I molecules, respectively. The negative impact of R71D/D75R could not be alleviated by stimulation with longer dsRNAs, which is somewhat at odds with the result with another Ub-binding deficient mutant, K95E/E98R. It is possible that R71D/D75R has more severe defects (in Ub binding or perhaps in 2CARD structure), which could not be overcome by Ub-conjugation or filament formation. For comparison, we also used GST-2CARD, which has been widely used in previous studies–. Despite the fact that GST-2CARD cannot form filaments, its sensitivity to the mutations was equivalent to full-length RIG-I with 42 bp, rather than 21 bp dsRNA. This likely reflects the effect of the fusion partner, GST, which forms a constitutive dimer. Isolated 2CARD without GST is a very poor stimulant of IFN-β, thus could not be used in this study.
Electron density map (2Fo-Fc) was contoured at σ = 0.9. Surface types were defined in the 2D representation on the left (as in Fig. 3b). a, Proximal Ub occupies surfaces IV and V on 2CARD. Surface IV interacts with the hydrophobic patch (L8/I44/V70) of proximal Ub, whereas V interacts with a combination of hydrophilic (N60/Q62) and hydrophobic (F45/A46) residues of proximal Ub. b, The distal Ub bound to 2CARD(D) simultaneously occupies both surfaces VI and V, whereas distal Ub’s bound to 2CARD(B) and (C) occupy surface VI alone (due to the lack of adjacent V). The interaction between distal Ub and VI is identical no matter whether the same Ub forms an additional interaction with V. Thus, only the distal Ub–2CARD(D) interaction is shown. Surface VI forms a combination of hydrophilic and hydrophobic interactions with Q49/R42 and L8/I44/V70 on distal Ub, respectively. Surface V interacts with distal Ub in the same manner as with proximal Ub, forming contacts with F45/A46/N60/N62 of Ub. Additional interactions involving surface V were seen with F4/T66/H68 of both distal and proximal Ubs (not shown in a), but they appear less intimate than those involving F45/A46/N60/N62.
a, EMSA analysis of the 2CARD tetramer formation using fluorescently labelled 2CARD-S (50 μM) with increasing concentrations of K63-Ubn (n = 2, 4, 6, 8). Note that an additional higher concentration (1 mg ml−1) was included only for K63-Ub2 (red asterisk), due to its low efficiency to stimulate 2CARD tetramerization. With K63-Ub8, additional bands appeared above the tetramer band, possibly reflecting two or more 2CARD tetramers bridged by a single Ub chains. b, Molecular mass analysis of 2CARD in complex with K63-Ub3i using multi-angle light scattering (MALS) coupled to size exclusion chromatography (SEC). Molecular mass estimated for the complex is 112.5 kDa (± 6.7 kDa), which is consistent with a tetrameric 2CARD (92.8 kDa, 23.2 ± 0.9 kDa as a monomer) bound by a single chain of K63-Ub3 (21.4 ± kDa). This 4:1 binding ratio of 2CARD to Ub3 is further supported by the SDS–PAGE intensity analysis of the complex (purified from MALS-SEC above) using Krypton fluorescence stain (right) (mean ± s.d., n = 3), which suggests the molar ratio of 4.5:1 for 2CARD–Ub3. This result suggests the sufficiency of a single chain of K63-Ubn (n > = 3) for stabilizing the 2CARD tetramer, although it does not exclude potential binding of additional Ubs at saturating concentrations. Note that previous study suggesting 4:4 binding of 2CARD to Ubn (n = 3–6) was performed in a buffer lacking salt (20 mM Tris-HCl (pH 7.5) and 1 mM DTT), whereas the current study was performed with 150 mM NaCl (20 mM HEPES (pH 7.5) and 150 mM NaCl), which could be responsible for the divergent results. The sufficiency of the single chain of Ub3 for stabilizing the 2CARD tetramer suggests that multiple stoichiometries and Ubn binding configurations are possible, depending on the concentrations of 2CARD and Ubn as well as buffer compositions. See g for how a single chain of K63-Ub3 could stabilize the 2CARD tetramer. c, Six Ub binding sites (1–6) were occupied in the crystal structure, with a potential for binding of up to eight total Ub molecules in the 2CARD tetramer. Site 7 is equivalent to sites 2, 4 and 6, and thus is a bona fide Ub-binding site. Site 8 is a hypothetical Ub-binding site, as its interaction with Ub would simultaneously utilize surfaces IV and VII, instead of surfaces IV and V as in sites 1, 3 and 5. Mutations of VII (K169D/L173R) did not affect the signalling activity of RIG-I in cells based on the IFNβ reporter assay (right) (mean ± s.d., n = 3). Although this result suggests that surface VII (which only affects site 8, not 1–7) is not important, it does not exclude the possibility of site 8 serving as another Ub-binding site, as the loss of one out of 8 sites may not have a significant effect on the signalling outcome, d, A model of the 2CARD tetramer with all 8 potential Ub binding sites occupied. Ub bound to sites 7 and 8 (surface representation) were modelled by superposing 2CARDs bound to distal and proximal Ub onto 2CARD(A) and (D), respectively. Ub binding sites are numbered according to the 2D representation in c. Crystallographic packing prevents Ub occupancy of sites 7 and 8. Neighbouring molecules, which occlude the sites 7 (left) and 8 (right), are shown in grey surface. e, Two configurations to occupy 7 or 8 potential Ub-binding sites in the 2CARD tetramer using a single K63-Ubn chain. Ub-binding sites are numbered as in b. Ub labelled ‘S’ stands for the unbound Ub that serves as a spacer. The presence of spacer Ub is consistent with the observed activity of Ub4 with K63- and K48- mixed linkage in stimulating RIG-I 2CARD, as there is no geometric restriction to impose the linkage specificity for the spacer Ub. f, Minimal length of K63-Ubn chain that allows bridging of four 2CARDs by a single Ub chains. Four examples were shown, in which Ub chains start with 2CARD subunit A, B, C or D. Ub-binding sites are numbered as in b. Ub labelled ‘S’ stands for the unbound Ub that serves as a spacer, g, Two configurations that a single chain of K63-Ub3 can bridge three 2CARDs (without involvement of a spacer Ub).
a, Sequence alignment of RIG-I and MDA5 2CARD (using the program ClustalOmega). Residues in RIG-I involved in the 2CARD–2CARD interactions (surface Ia/b–IIIa/b in Extended Data Fig. 4) and Ub binding (surface IV, V and VI in Extended Data Fig. 6), and their equivalent residues in MDA5 are highlighted (yellow and green for 2CARD–2CARD and 2CARD–Ub interfaces, respectively). Residue numbers right above highlights are according to human RIG-I. Residues tested by mutagenesis in this study are indicated by blue colour. Residues involved in the 2CARD–2CARD interactions show, on average, a moderate level of conservation in comparison to other residues on the surface of RIG-I 2CARD (see surface representation in b). Poor conservation of the tetramerization interface is consistent with previous observations that protein-protein interfaces often display evolutionary versatility due to the plasticity of the interaction and co-evolution of the interacting surfaces,. The Ub binding surface of RIG-I is more conserved than the 2CARD–2CARD interface (see surface representation in b), possibly reflecting the conserved nature of Ub. When the comparison is made between RIG-I and MDA5, we found that only four residues are well-conserved (F12 and L110 in the Ub-binding surface, and E36 and K164 in tetramerization surface), assuming interchange of residues within each group of F/Y, L/V/I or D/E as well-conserved. This is insufficient to support structural conservation of the 2CARD tetramer or 2CARD–Ub complex between RIG-I and MDA5. The structure of the MDA5 oligomers and/or MDA5–Ub complex would be required to compare 2CARD oligomerization mechanism between RIG-I and MDA5. b, Degree of sequence conservation (within RIG-I based on a) mapped onto the RIG-I 2CARD tetramer structure (generated using the program Chimera). Consistent with the analysis above, the 2CARD–2CARD interfaces show a moderate level of conservation, whereas Ub-binding sites show a higher degree of conservation. Other conserved surface areas may be involved in interactions with other molecules, such as TRIM25 or MAVS.
Structure-based sequence alignment (using the program SALGIN) of various CARD domains. In our effort to further analyse potential generality of 2CARD–Ub interaction observed with RIG-I in our structure, we aligned other CARDs with RIG-I 2CARD. We performed structure-based sequence alignment, as many members of the CARD family share little sequence similarity. Three dimensional protein structure, which is more conserved than the primary sequence, allows more accurate sequence comparison. The first CARD (a) and second CARD (b) of human RIG-I was aligned with other CARDs from MAVS, APAF1, Iceberg and NOD1 (PDB code: 2VGQ, 3YGS, 1DGN and 4E9M, respectively). None of the Ub-binding residues in RIG-I 2CARD are conserved in these CARDs.
a, Domain architecture of RIG-I and top and side views of the 2CARD tetramer (chains A–D, surface representation) bound by Ub chains (cartoon representation). The second CARDs are demarcated by black lines, b, Two-dimensional (2D) representation and ‘lock-washer model of the RIG-I 2CARD tetramer, using the same colour code as for a. c, Definition of the surface types in the first and second CARDs. Six types of intermolecular interactions were observed; three in the A–B, B–C and C–D interactions (solid lines on the right), and another three in the D–A interaction (dotted lines). A single type of intramolecular interaction was observed between IIb of the first CARD and IIa of the second CARD (curved line). See Extended Data Fig. 4. d, Tetramer formation of wild-type and mutant 2CARD fused to an Alexa647-labelled SNAP tag (2CARD-S) with and without K63-Ubn (n > 8) as measured by EMSA. Mutations are on the indicated surface as defined in c.
a, A ‘helical extension’ model for how the RIG-I 2CARD tetramer stimulates the MAVS CARD (grey) filament formation. b, D122 and E178/R179 are located at the top of the 2CARD tetramer (surface IIb of the second CARD), whereas Q65 and E66 are at the bottom of the 2CARD tetramer (surface IIa of the first CARD), c, IFN-β signalling activity of mutants with altered surface IIa or IIb of the first and second CARDs (mean ± s.d., n = 3). d, e, 2CARD tetramerization (d) and MAVS filament stimulation (e) of wild-type RIG-I 2CARD and its mutants. The SNAP-fusion allowed fluorescent labelling (indicated with an asterisk) of RIG-I 2CARD and MAVS CARD (2CARD-S and CARD-S, respectively), f, g, Filament formation (f) and IFN-β signalling activity (g) (mean ± s.d., n = 3) of wild-type MAVS and its mutants with altered surface I–IIIa/b.
a, Two types of Ub–2CARD interactions. Proximal Ub forms a composite interaction with two adjacent 2CARDs using two surface areas (purple and orange spheres). Distal Ub interacts with only one 2CARD using one of the two surface areas (brown spheres), with the exception of Ub bound to D. Dotted lines represent disordered K63-linkers between proximal and distal Ubs. See Extended Data Fig. 6. b, Three types of 2CARD surface areas (IV, V and VI) are involved in Ub binding. Surface IV and VI interact with L8/I44/V70 in proximal and distal Ubs, respectively, whereas surface V interacts with F45/A46/N60/N62 of proximal Ub. Mapping of IV–VI onto the 2D representation of the 2CARD tetramer revealed 7 bona fide Ub binding sites, six of which (sites 1–6) are occupied in our structure, and one potential binding site (site 8, see Extended Data Fig. 7c, d for additional discussion). Single and double lines indicate respectively the distance between adjacent Ubs that can be directly connected through a K63-linkage and those that cannot (thus requiring a spacer Ub). c, EMSA analysis of the tetramer formation by wild-type RIG-I 2CARD-S and its mutants with altered surfaces IV, V and IV, upon incubation with K63-Ubn (n > 8). d, IFN-β reporter activity of wild-type and mutant RIG-I 2CARD in GST fusion (mean ± s.d., n = 3).
a, The C-terminal residue of the proximal Ub is within the covalent-linkage distance from the target Lys. As residues 72–76 of proximal Ub were disordered in the structure, distance was measured between Cαs of L71 in proximal Ub (red sphere) and target Lys (K99, K169, K172 andK181, black spheres) in 2CARD. V188 was used in place of K190 and K193, which are in the disordered C-terminal tail of 2CARD. The distance requirement for covalent conjugation (<25Å) is shown on the right, b, EMSA analysis of 2CARD tetramerization stimulated by covalently conjugated or unanchored K63-Ub2 or Ub1. Fluorescently labelled (indicated with an asterisk) 2CARD-S was subject to Ub conjugation (TRIM25 reaction) before or after EDTA quenching. Samples 3 and 5 enable direct comparison between covalently conjugated and unanchored Ub2. As elongation of Ub chains by TRIM25 is prevented by K63R mutation within Ub2 and Ub1, the presence of several bands in SDS–PAGE analysis reflects conjugation of Ub2 to 2CARD at multiple Lys targets, c, Comparison of the MAVS stimulatory activity of 2CARD covalently conjugated with K63-Ub2 (sample 3 from b) or 2CARD with unanchored K63-Ub2 (sample 5 from b). Increasing concentrations of 2CARD-S (47 or 187 or 750 or 3000 nM) were incubated with fluorescently labelled monomeric MAVS CARD-S and MAVS filament formation was monitored by BMSA. d, EMSA analysis of tetramerization of mutant 2CARD by covalently conjugated (sample 3 from (b)) or unanchored K63-Ub2 (sample 5 from (b)).
Comment in
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The lock-washer: a reconciliation of the RIG-I activation models.Cell Res. 2014 Jun;24(6):645-6. doi: 10.1038/cr.2014.58. Epub 2014 May 6. Cell Res. 2014. PMID: 24797430 Free PMC article.
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