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Dynamic interactions and Ca2+-binding modulate the holdase-type chaperone activity of S100B preventing tau aggregation and seeding

Moreira, Guilherme G., Cantrelle, François-Xavier, Quezada, Andrea, Carvalho, Filipa S., Cristóvão, Joana S., Sengupta, Urmi, Puangmalai, Nicha, Carapeto, Ana P., Rodrigues, Mário S., Cardoso, Isabel, Fritz, Güenter, Herrera, Federico, Kayed, Rakez, Landrieu, Isabelle, Gomes, Cláudio M.·2021·Nature Communications
DOI 10.1038/s41467-021-26584-2PMC PMC8560819
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Abstract

The microtubule-associated protein tau is implicated in the formation of oligomers and fibrillar aggregates that evade proteostasis control and spread from cell-to-cell. Tau pathology is accompanied by sustained neuroinflammation and, while the release of alarmin mediators aggravates disease at late stages, early inflammatory responses encompass protective functions. This is the case of the Ca 2+-binding S100B protein, an astrocytic alarmin which is augmented in AD and which has been recently implicated as a proteostasis regulator, acting over amyloid β aggregation. Here we report the activity of S100B as a suppressor of tau aggregation and seeding, operating at sub-stoichiometric conditions. We show that S100B interacts with tau in living cells even in microtubule-destabilizing conditions. Structural analysis revealed that tau undergoes dynamic interactions with S100B, in a Ca 2+-dependent manner, notably with the aggregation prone repeat segments at the microtubule binding regions. This interaction involves contacts of tau with a cleft formed at the interface of the S100B dimer. Kinetic and mechanistic analysis revealed that S100B inhibits the aggregation of both full-length tau and of the microtubule binding domain, and that this proceeds through effects over primary and secondary nucleation, as confirmed by seeding assays and direct observation of S100B binding to tau oligomers and fibrils. In agreement with a role as an extracellular chaperone and its accumulation near tau positive inclusions, we show that S100B blocks proteopathic tau seeding. Together, our findings establish tau as a client of the S100B chaperone, providing evidence for neuro-protective functions of this inflammatory mediator across different tauopathies.

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Figures

Fig. 1 S100B and tau colocalize in living cells and interactions persist upon microtubule destabilization. a Representation of N- and C-terminal halves of Venus constructs fused to tau and S100B termini and gain of fluorescence based on bimolecular fluorescence complementation. b HeLa cells were transfected with the BiFC constructs tau/tau and S100B/tau and incubated with 10 µM of nocodazole for 16 h. Nocodazole was then removed, and cells were visualized immediately after washing out nocodazole (t = 0) in time lapse for 30 min. Scale bar: 20 µm. c, d Wide-field microscopy and super-resolution radial fluctuations (SRRF) reconstruction of HeLa cells (c) after 24 h of transient transfection with the BiFC constructs tau/tau and S100B/tau; and (d) after 16 h of incubation with 10 µM of nocodazole, imaged ~15 min after washout. Scale bar: 20 µm. e Violin-plot representation of cells forming puncta (top panel) and number of puncta per cell (bottom panel) after 16 h of incubation with 10 µM of nocodazole. Plots are presented with floating boxes showing mean (white dot) and 1st and 3rd quartiles (floating black boxes). Minimum and maximum values of the distribution are shown as the bottom and top of the violin plot. The number of cells analyzed was 927 (tau/tau) and 873 (tau/S100B) in a total of 65 pictures/group from 4 independent experiments. Data were analyzed by means of a two-tailed t–student test. *, significant versus tau/tau, top p = 0.0097 and bottom p = 3.6673 × 10−34.
Fig. 1 S100B and tau colocalize in living cells and interactions persist upon microtubule destabilization. a Representation of N- and C-terminal halves of Venus constructs fused to tau and S100B termini and gain of fluorescence based on bimolecular fluorescence complementation. b HeLa cells were transfected with the BiFC constructs tau/tau and S100B/tau and incubated with 10 µM of nocodazole for 16 h. Nocodazole was then removed, and cells were visualized immediately after washing out nocodazole (t = 0) in time lapse for 30 min. Scale bar: 20 µm. c, d Wide-field microscopy and super-resolution radial fluctuations (SRRF) reconstruction of HeLa cells (c) after 24 h of transient transfection with the BiFC constructs tau/tau and S100B/tau; and (d) after 16 h of incubation with 10 µM of nocodazole, imaged ~15 min after washout. Scale bar: 20 µm. e Violin-plot representation of cells forming puncta (top panel) and number of puncta per cell (bottom panel) after 16 h of incubation with 10 µM of nocodazole. Plots are presented with floating boxes showing mean (white dot) and 1st and 3rd quartiles (floating black boxes). Minimum and maximum values of the distribution are shown as the bottom and top of the violin plot. The number of cells analyzed was 927 (tau/tau) and 873 (tau/S100B) in a total of 65 pictures/group from 4 independent experiments. Data were analyzed by means of a two-tailed t–student test. *, significant versus tau/tau, top p = 0.0097 and bottom p = 3.6673 × 10−34.CC BY · PubMed Central
Fig. 2 Mapping S100B interactions to tau. a, b 2D 1H,15N HSQC spectra of 100 µM 15N-tau alone (black), in the presence of 120 µM S100B and 1.25 mM EDTA (a, blue), or in the presence of 120 µM S100B and 250 µM CaCl2 (b, orange). c, d Detail of HSQC-NMR spectra evidencing tau-resonance perturbations corresponding to residues affected by S100B binding. Parts per million (ppm). e Schematic representation of full-length tau highlighting the PRR and MTBR as well as the repeat regions R1–R4 and the aggregation-prone segments PHF6* and PHF6, aligned with the x axis of plots f and g. f, g Intensity variation of each tau resonance in the presence of S100B and in the presence (f, orange) or the absence (g, blue) of calcium. Ratio of peak intensity over initial peak intensity (I/I0).
Fig. 2 Mapping S100B interactions to tau. a, b 2D 1H,15N HSQC spectra of 100 µM 15N-tau alone (black), in the presence of 120 µM S100B and 1.25 mM EDTA (a, blue), or in the presence of 120 µM S100B and 250 µM CaCl2 (b, orange). c, d Detail of HSQC-NMR spectra evidencing tau-resonance perturbations corresponding to residues affected by S100B binding. Parts per million (ppm). e Schematic representation of full-length tau highlighting the PRR and MTBR as well as the repeat regions R1–R4 and the aggregation-prone segments PHF6* and PHF6, aligned with the x axis of plots f and g. f, g Intensity variation of each tau resonance in the presence of S100B and in the presence (f, orange) or the absence (g, blue) of calcium. Ratio of peak intensity over initial peak intensity (I/I0).CC BY · PubMed Central
Fig. 3 Mapping tau interactions to S100B. a Zoom of HSQC spectra evidencing chemical shift perturbation of 100 µM 15N-S100B residues in the presence of 1.25 mM CaCl2 and 160 µM full-length tau (green), 100 µM K18 (or MTBR, red), 250 µM of R2 (blue) and R3 peptide (yellow). Spectra changes upon binding of tau (green), K18 (red), and R2 (blue) and R3 (yellow) peptides to S100B-Ca2+ (alone in gray). b Plots of the chemical shift perturbation along S100B sequence following addition (from top to bottom) of full-length tau (molar ratio 1:1.6), tau K18 fragment (molar ratio 1:1), and tau peptides (molar ratio 1:2.5). Peaks broadened beyond detection are represented with a fixed arbitrary value of 0.2 (with tau) and 0.5 (with K18). Parts per million (ppm). A scheme of the secondary structures of S100B is presented above the plots, scaled according to the sequence of the x axis. c 3D mapping of the R2:S100B-Ca2+ spectral perturbations identified the S100B dimer interfacial clef (dotted box) involving helix IV as the major attachment point, chemical shift perturbations (as in a) are color-coded on the protein surface [Protein Data Bank (PDB) code: 2H61]. See Methods for details, Supplementary Figs 7 and 9 and Supplementary Movie 1. d Ab initio SAXS-derived envelopes of S100B-Ca2+:K18 complex (blue) and S100B-Ca2+ (red), see Supplementary Table 1 for data-collection and scattering-derived parameters. The crystal structure of S100B-Ca2+ fitted to both molecular envelopes is shown in cartoon representation.
Fig. 3 Mapping tau interactions to S100B. a Zoom of HSQC spectra evidencing chemical shift perturbation of 100 µM 15N-S100B residues in the presence of 1.25 mM CaCl2 and 160 µM full-length tau (green), 100 µM K18 (or MTBR, red), 250 µM of R2 (blue) and R3 peptide (yellow). Spectra changes upon binding of tau (green), K18 (red), and R2 (blue) and R3 (yellow) peptides to S100B-Ca2+ (alone in gray). b Plots of the chemical shift perturbation along S100B sequence following addition (from top to bottom) of full-length tau (molar ratio 1:1.6), tau K18 fragment (molar ratio 1:1), and tau peptides (molar ratio 1:2.5). Peaks broadened beyond detection are represented with a fixed arbitrary value of 0.2 (with tau) and 0.5 (with K18). Parts per million (ppm). A scheme of the secondary structures of S100B is presented above the plots, scaled according to the sequence of the x axis. c 3D mapping of the R2:S100B-Ca2+ spectral perturbations identified the S100B dimer interfacial clef (dotted box) involving helix IV as the major attachment point, chemical shift perturbations (as in a) are color-coded on the protein surface [Protein Data Bank (PDB) code: 2H61]. See Methods for details, Supplementary Figs 7 and 9 and Supplementary Movie 1. d Ab initio SAXS-derived envelopes of S100B-Ca2+:K18 complex (blue) and S100B-Ca2+ (red), see Supplementary Table 1 for data-collection and scattering-derived parameters. The crystal structure of S100B-Ca2+ fitted to both molecular envelopes is shown in cartoon representation.CC BY · PubMed Central
Fig. 4 S100B-Ca2+ inhibits full-length tau and K18-fragment aggregation. a, b Fibril formation of 25 µM hTau441 (red) in 50 mM Tris, pH 7.4, in the absence (a) or the presence (b) of 1.1 mM CaCl2 at 37 °C under agitation in the presence of 0.5 (orange), 1.0 (yellow), and 4.0 (green) molar equivalents of S100B. Aggregation induced by 0.5 mg/mL heparin addition. c, d AFM (left) and TEM (right) imaging of end-time species of hTau441 aggregation in the absence (c) or the presence (d) of Ca2+ at 10 µM tau and at a S100B:tau molar ratio of 1. Scale bars, 200 µm (c) and 500 µm (d). Independent experiments of AFM and TEM morphological analysis were performed at least three times. e, f Fibril formation of 10 µM K18 (red) in 50 mM Tris, pH 7.4, in the absence (e) or the presence (f) of 1.1 mM CaCl2 at 37 °C under agitation in the presence of 0.01 (orange), 0.05 (yellow), 0.1 (green), 0.2 (light blue), 0.3 (purple), 0.5 (blue), 1.0 (gray), and 4.0 (dark blue) molar equivalents of S100B. Aggregation induced by 90 µg/mL heparin addition. Plots represent averaged normalized intensity curves obtained from three independent replicates for each of the tested conditions. g ThT intensity in arbitrary units (arb. units) of end-time point K18 aggregation in the presence of 1.1 mM CaCl2 (same color code); h half-time of K18 aggregation in the absence (blue) or the presence (light pink) of 1.1 mM CaCl2. Data are presented as mean values ± SD from n = 3 independent experiments except for samples with 0.1 and 0.3 equivalents of S100B for which n = 2. See Methods for details.
Fig. 4 S100B-Ca2+ inhibits full-length tau and K18-fragment aggregation. a, b Fibril formation of 25 µM hTau441 (red) in 50 mM Tris, pH 7.4, in the absence (a) or the presence (b) of 1.1 mM CaCl2 at 37 °C under agitation in the presence of 0.5 (orange), 1.0 (yellow), and 4.0 (green) molar equivalents of S100B. Aggregation induced by 0.5 mg/mL heparin addition. c, d AFM (left) and TEM (right) imaging of end-time species of hTau441 aggregation in the absence (c) or the presence (d) of Ca2+ at 10 µM tau and at a S100B:tau molar ratio of 1. Scale bars, 200 µm (c) and 500 µm (d). Independent experiments of AFM and TEM morphological analysis were performed at least three times. e, f Fibril formation of 10 µM K18 (red) in 50 mM Tris, pH 7.4, in the absence (e) or the presence (f) of 1.1 mM CaCl2 at 37 °C under agitation in the presence of 0.01 (orange), 0.05 (yellow), 0.1 (green), 0.2 (light blue), 0.3 (purple), 0.5 (blue), 1.0 (gray), and 4.0 (dark blue) molar equivalents of S100B. Aggregation induced by 90 µg/mL heparin addition. Plots represent averaged normalized intensity curves obtained from three independent replicates for each of the tested conditions. g ThT intensity in arbitrary units (arb. units) of end-time point K18 aggregation in the presence of 1.1 mM CaCl2 (same color code); h half-time of K18 aggregation in the absence (blue) or the presence (light pink) of 1.1 mM CaCl2. Data are presented as mean values ± SD from n = 3 independent experiments except for samples with 0.1 and 0.3 equivalents of S100B for which n = 2. See Methods for details.CC BY · PubMed Central
Fig. 5 S100B-Ca2+ inhibits tau surface-catalyzed secondary nucleation and colocalizes with tau fibrils and oligomers. a Seeded fibril formation of 10 µM hTau441 (red) in 50 mM Tris pH 7.4, in the presence of 0.005% of preformed fibrils and 1.1 mM CaCl2 at 37 °C under agitation, in the presence of 0.1 (orange), 0.2 (yellow), 0.4 (green), 0.6 (light blue), 0.8 (purple), 1.0 (blue), 2.0 (gray), and 4.0 (dark blue) molar equivalents of S100B. b ThT intensity in arbitrary units (arb. units) of the end-time point (same color code) and half-time reaction (inset) of the hTau441-seeded aggregation in the presence (light pink) or the absence (blue) of Ca2+, for different S100B molar equivalents. c hTau441-seeded aggregation in the same conditions with addition of equimolar S100B at 0 (gray), 5 (light blue, 1), 25 (dark blue, 2), and 50 (blue, 3) hours after aggregation start. Data are presented as mean values ± SD from n = 3 independent experiments except for samples with 0.0 and 0.1 equivalents of S100B for which n = 2. d–f TEM images of tau aggregates grown in the presence of S100B-Ca2+ and immunogold labeled against S100B (10 nm, arrow) and tau (15 nm, arrowhead). d Zoom from the black box in e. S100B bound to tau small aggregates and oligomers (boxes in f). Scale bar 100 nm (e and f). Independent experiments of immunogold labeling were performed three times.
Fig. 5 S100B-Ca2+ inhibits tau surface-catalyzed secondary nucleation and colocalizes with tau fibrils and oligomers. a Seeded fibril formation of 10 µM hTau441 (red) in 50 mM Tris pH 7.4, in the presence of 0.005% of preformed fibrils and 1.1 mM CaCl2 at 37 °C under agitation, in the presence of 0.1 (orange), 0.2 (yellow), 0.4 (green), 0.6 (light blue), 0.8 (purple), 1.0 (blue), 2.0 (gray), and 4.0 (dark blue) molar equivalents of S100B. b ThT intensity in arbitrary units (arb. units) of the end-time point (same color code) and half-time reaction (inset) of the hTau441-seeded aggregation in the presence (light pink) or the absence (blue) of Ca2+, for different S100B molar equivalents. c hTau441-seeded aggregation in the same conditions with addition of equimolar S100B at 0 (gray), 5 (light blue, 1), 25 (dark blue, 2), and 50 (blue, 3) hours after aggregation start. Data are presented as mean values ± SD from n = 3 independent experiments except for samples with 0.0 and 0.1 equivalents of S100B for which n = 2. d–f TEM images of tau aggregates grown in the presence of S100B-Ca2+ and immunogold labeled against S100B (10 nm, arrow) and tau (15 nm, arrowhead). d Zoom from the black box in e. S100B bound to tau small aggregates and oligomers (boxes in f). Scale bar 100 nm (e and f). Independent experiments of immunogold labeling were performed three times.CC BY · PubMed Central
Fig. 6 S100B inhibits toxic seeding mediated by tau oligomers. a, b Representative immunofluorescence images of tau RD P301S FRET biosensor cells exposed to tau oligomers (0.1 µM and 0.5 µM) alone (a) or to tau oligomers preincubated with S100B (5 µM) (b) for 24 h in the presence of lipofectamine. In all, 5 µM S100B data are shown as representative data of the effect of S100B alone in tau biosensor cells, as even higher concentrations did not cause seeding. Cell nuclei stained with DAPI (blue). Objective used: 40X; scale bar 50 μm. c Statistical analysis with data presented as mean and standard error of mean from n ≥ 3 independent experimental replicates using one-way analysis of variance (ANOVA) with Tukey’s multiple-comparison test. Specifically, for assays with vehicle and 5 µM S100B n = 3, for assays with 0.1 µM TauO n = 5, for assays with 0.5 µM TauO n = 4, and for assays with 5 µM S100B + 0.1 µM TauO and 5 µM S100B + 0.5 µM TauO n = 6. Statistical significance at p < 0.05 was considered, ****p < 0.0001 and ***p = 0.0009.
Fig. 6 S100B inhibits toxic seeding mediated by tau oligomers. a, b Representative immunofluorescence images of tau RD P301S FRET biosensor cells exposed to tau oligomers (0.1 µM and 0.5 µM) alone (a) or to tau oligomers preincubated with S100B (5 µM) (b) for 24 h in the presence of lipofectamine. In all, 5 µM S100B data are shown as representative data of the effect of S100B alone in tau biosensor cells, as even higher concentrations did not cause seeding. Cell nuclei stained with DAPI (blue). Objective used: 40X; scale bar 50 μm. c Statistical analysis with data presented as mean and standard error of mean from n ≥ 3 independent experimental replicates using one-way analysis of variance (ANOVA) with Tukey’s multiple-comparison test. Specifically, for assays with vehicle and 5 µM S100B n = 3, for assays with 0.1 µM TauO n = 5, for assays with 0.5 µM TauO n = 4, and for assays with 5 µM S100B + 0.1 µM TauO and 5 µM S100B + 0.5 µM TauO n = 6. Statistical significance at p < 0.05 was considered, ****p < 0.0001 and ***p = 0.0009.CC BY · PubMed Central
Fig. 7 Proposed model for the intra- and extracellular action of the S100B chaperone on tau. The cartoon summarizes regulatory intra- (left) and extracellular (right) interactions established between S100B and tau. Inside cells, S100B operates as a microtubule-regulating factor, likely acting as a protective holdase that mitigates proteotoxic tau, upon its release following microtubule destabilization. Extracellular S100B is increased in the AD brain from early disease stages and is abundantly secreted by astrocytes nearby tau-positive inclusions. In this context, S100B performs as a chaperone inhibiting aggregation through interactions established with released proteotoxic tau, thus contributing to decrease seeding reactions and pathological cell-to-cell spreading.
Fig. 7 Proposed model for the intra- and extracellular action of the S100B chaperone on tau. The cartoon summarizes regulatory intra- (left) and extracellular (right) interactions established between S100B and tau. Inside cells, S100B operates as a microtubule-regulating factor, likely acting as a protective holdase that mitigates proteotoxic tau, upon its release following microtubule destabilization. Extracellular S100B is increased in the AD brain from early disease stages and is abundantly secreted by astrocytes nearby tau-positive inclusions. In this context, S100B performs as a chaperone inhibiting aggregation through interactions established with released proteotoxic tau, thus contributing to decrease seeding reactions and pathological cell-to-cell spreading.CC BY · PubMed Central

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Cited by

Metadata

Authors
Moreira, G. G., Cantrelle, F.-X., Quezada, A., Carvalho, F. S., Cristóvão, J. S., Sengupta, U., Puangmalai, N., Carapeto, A. P., Rodrigues, M. S., Cardoso, I., Fritz, G., Herrera, F., Kayed, R., Landrieu, I., & Gomes, C. M.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-11-01
Volume
12
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-021-26584-2
PMC
PMC8560819
Cited by
47
References
7
Language
en
Licence

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