Abstract
To cope with proteotoxic stress, cells attenuate protein synthesis. However, the precise mechanisms underlying this fundamental adaptation remain poorly defined. Here we report that mTORC1 acts as an immediate cellular sensor of proteotoxic stress. Surprisingly, the multifaceted stress-responsive kinase JNK constitutively associates with mTORC1 under normal growth conditions. On activation by proteotoxic stress, JNK phosphorylates both RAPTOR at S863 and mTOR at S567, causing partial disintegration of mTORC1 and subsequent translation inhibition. Importantly, HSF1, the central player in the proteotoxic stress response (PSR), preserves mTORC1 integrity and function by inactivating JNK, independently of its canonical transcriptional action. Thereby, HSF1 translationally augments the PSR. Beyond promoting stress resistance, this intricate HSF1–JNK–mTORC1 interplay, strikingly, regulates cell, organ and body sizes. Thus, these results illuminate a unifying mechanism that controls stress adaptation and growth.
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Acknowledgements
We would like to thank members of the Dai laboratory for discussions and technical assistance. This work was supported by a grant from the NIH (1DP1OD006438) to I.J.B.; and The Jackson Laboratory Cancer Center Support Grant (3P30CA034196), and grants from the NIH (1DP2OD007070) and the Ellison Medical Foundation (AS-NS-0599-09) to C.D.
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K.-H.S., J.C., Z.T. and S.D. designed and performed the experiments. Y.H. performed statistical analyses and generated graphs. I.J.B. provided mice and cell lines and actively engaged in discussions. C.D. conceived and oversaw this study. S.B.S. and C.D. wrote the manuscript.
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Integrated supplementary information
Supplementary Figure 1 Perturbation of proteostasis by proteotoxic stressors, related to Fig. 1.
(a) Proteotoxic stressors perturb proteostasis via diverse mechanisms of action. Ub: ubiquitin. (b) HEK293T cells were treated with diverse proteotoxic stressors at the concentrations described in Fig. 1B and 1C for 4 and 8 h. Cell viability was measured by a Guava EasyCyte cytometer using ViaCount reagents (mean of 4 wells of cells per group from one experiment). (c) HEK293T cells were treated with 500 nM MG132 for indicated time. JNK and p38 MAPK phosphorylation were detected by immunoblotting. (d) Following pre-incubation with 10 μM SB202190 for 30 min, HEK293T cells were treated with 500 nM MG132 for indicated time. Phosphorylation of p38 MAPK and mTORC1 signalling were detected by immunoblotting. Uncropped images of blots are shown in Supplementary Fig. 8. Source data for Supplementary Fig. 1b can be found in Supplementary Table 1.
Supplementary Figure 2 JNK is a negative regulator of mTORC1 signalling, translation, and cell size, related to Fig. 2.
(a) HEK293T cells stably transduced with lentiviral scramble or JNK1/2-targeting shRNAs were treated with and without 500 nM MG132 for 4 h. Phosphorylated and total JNK1/2 levels were detected by immunoblotting. (b) Following pre-incubation with 3 μM JNK-IN-8 for 60 min, HEK293T cells were treated with and without 500 nM MG132 for 4 h. Endogenous mTOR-RAPTOR associations and mTORC1 kinase activity were measured by coIP. (c) and (d) Primary MEFs were treated with 200 nM MG132 for 6 h, and cell viability was measured using ViaCount reagents (mean of6 wells of cells per group from one experiment). (e) Following transfection with 10 nM three independent MKK7-targetting siRNAs for 4 days, MKK7 and phosphorylated S6K proteins were detected by immunoblotting in HEK293T cells. (f) Following pre-incubation with 3 μM JNK-IN-8 for 60 min, phosphorylated S6K proteins were detected by immunoblotting in HEK293T cells transfected with LacZ, JNK1CA, or JNK2A2 plasmid. (g) Endogenous mTOR-RAPTOR associations were detected by coIP in HEK293T cells transfected with LacZ, JNK1CA, or JNK2A2 plasmid. (h) Following 1 μM AZD8055 treatment overnight, HEK293T cells were labelled with 6-FAM-dc-puromycin for 30 min and analysed by flow cytometry. Unlabelled cells served as negative controls. (i) Following transfection with JNK1/2-targeting siRNAs (A: siJNK1_2 and siJNK2_2; B: siJNK1_3 and siJNK2_3), total JNK1/2 levels were detected by immunoblotting. (j) Following transfection with indicated plasmids, HeLa cells were treated with DMSO or 1 μM AZD8055 for 2 days and analysed for cell size using a Multisizer 3 Coulter Counter. Changes in cell size distribution, compared to the LacZ control, are statistically significant (Kolmogorov-Smirnov test, P < 0.01). (k) and (l) JNK and mTORC1 signalling were detected by immunoblotting in mouse skin and kidneys. (m)–(o) Whole-body weight and composition were measured in 6-week-old male mice (mean ± s.d., n = 5, 5, or 6 mice per genotype, One-way ANOVA). Statistical significance: ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001; n.s.: not significant. Uncropped images of blots are shown in Supplementary Fig. 8. Source data for Supplementary Fig. 2c, d can be found in Supplementary Table 1.
Supplementary Figure 3 JNK physically interacts with RAPTOR and mTOR, related to Fig. 3.
(a)–(c) Validations of mouse monoclonal anti-JNK1 (JM2671), rabbit monoclonal anti-mTOR (7C10), and mouse monoclonal anti-RAPTOR (1H6.2) antibodies by immunostaining in HeLa cells stably expressing shRNAs. Scale bars: 50 μm. Images are representative of 2 independent experiments. (d) Endogenous mTORC1 was precipitated using anti-RAPTOR antibodies from HEK293T cells. Precipitates were resolved on SDS-PAGE under non-reducing conditions. Precipitated mTORC1 components were visualized by silver staining (Silver Stain Kit, Thermo Fisher Scientific). To avoid obscuring of mTOR by the staining of abundant whole IgG, the portion containing IgG was separated from the rest of the gel and stained for less time. The rest of the gel was silver-stained for the same period of time to reveal both mTOR and JNK proteins. The p46 isoforms of JNK proteins could not be clearly identified due to the obscuration by IgG heavy chains (HC). MK: molecular weight marker. The staining intensities of mTOR and JNK proteins were quantitated by ImageJ software, and normalized against their total numbers of amino acids. (e) The consensus JNK phosphorylation sequence is derived from curated JNK substrates (www.phosphosite.org) and plotted using the online WebLoGo software (www.weblogo.berkeley.edu). Predicted JNK phosphorylation sites, RAPTOR Ser863 and mTOR Ser567, are highlighted in red. (f) Endogenous mTORC1 complexes were immunoprecipitated from HEK293T cells. Immediately following addition of 100 ng recombinant GST or GST-JNK1 proteins to equal amounts of precipitates, indicated concentrations of JNK-IN-8 (JIN8) or AZD8055 (AZD) were added to the kinase mixtures and incubated at 30 °C for 30 min for in vitro JNK kinase assays. (g) and (h) Following treatment with 500 nM MG132 for 4 h, endogenous RAPTOR and mTOR proteins were precipitated from HEK293T cells stably expressing scramble or JNK1/2-targeting shRNAs. RAPTOR Ser863 and mTOR Ser567 phosphorylation was detected by immunoblotting. (i) and (j) HEK293T cells depleted of endogenous RAPTOR or mTOR proteins due to stably shRNA expression were transfected with indicated plasmids and treated with DMSO or 500 nM MG132 for 4 h. JNK and mTORC1 signalling were detected by immunoblotting.
Supplementary Figure 4 HSF1 suppresses JNK activation and sustains mTORC1 signalling, related to Figs 4 and 5.
(a) Schematic depiction of the generation of conditional Hsf1fl/fl alleles on the C57BL/6J genetic background. Expression of Cre recombinase results in deletion of exon2-9 (Δ2-9) of the Hsf1 gene. (b) Cells were treated as described in Fig. 4A. Cell viability was measured by a Guava EasyCyte cytometer using ViaCount reagents (mean of4 or 5 wells of cells per group from one experiment). (c) Validations of rabbit polyclonal anti-JNK1/3 (C-17) and mouse monoclonal anti-HSF1 (E-4) antibodies by immunostaining in primary Jnk1+/+ and Jnk1−/− MEFs (left panel), and in immortalized Rosa26-CreERT2; Hsf1fl/fl MEFs treated with 1 μM 4-OHT or EtOH for 7 days (right panel). Scale bars: 50 μm. (d) Endogenous HSF1-JNK1 interactions were detected by PLA in immortalized Rosa26-CreERT2; Hsf1fl/fl MEFs treated with and without 1 μM 4-OHT for 7 days, using mouse anti-HSF1 (E-4) and rabbit anti-JNK1/3 (C-17) antibodies. Scale bars: 10 μm. (e) HEK293T cells were transfected with LacZ or FLAG-tagged HSF1 plasmids. Following IP of endogenous JNK1 proteins, co-precipitated FLAG-tagged HSF1 and endogenous RAPTOR proteins were immunoblotted. (f) Schematic depiction of the proposed sequestration of JNK apart from mTORC1 by HSF1. Uncropped images of blots are shown in Supplementary Fig. 8. Source data for Supplementary Fig. 4b can be found in Supplementary Table 1.
Supplementary Figure 5 mTORC1 inhibition suppresses the PSR, related to Fig. 6.
HEK293T cells were treated with the mTORC1 inhibitor rapamycin (100 nM) or AZD8055 (1 μM) overnight. Translation rates of HSF1 were measured by puromycin labelling as described in Fig. 5b (mean of 6 wells of cells per group per experiment, and this experiment was repeated twice). Source data for Supplementary Fig. 5 can be found in Supplementary Table 1.
Supplementary Figure 6 HSF1 is a positive regulator of cell, organ, and body sizes, related to Fig. 7.
(a) and (b) HEK293T cells were co-transfected with indicated shRNAs and siRNAs. HSF1 and JNK1/2 levels were detected by immunoblotting (a), and protein synthesis rates were measured by puromycin labelling (b). (c) Livers of female mice were weighed at 6 weeks of age (mean ± s.d., n = 6, 7, or 8 mice per genotype, One-way ANOVA). (d) HSP90α, HSP72, and HSP25 proteins were detected by immunoblotting in mouse livers. (e) and (f) Kidneys of male mice were weighed at 6 weeks of age (mean ± s.d., n = 4 mice per genotype, One-way ANOVA). (g) Digital photos of female mice at 6 weeks of age were taken and body surface areas were quantitated by ImageJ software (mean ± s.d., n = 3 mice per genotype, One-way ANOVA). (h) and (i) Body weights were measured in female mice at 6 weeks of age (mean ± s.d., n = 6, 13, 16, or 34 mice per genotype, One-way ANOVA). (j) and (k) Whole-body composition was measured in female mice at 6 weeks of age (mean ± s.d., n = 6, 7, or 18 mice per genotype, One-way ANOVA). Statistical significance: ∗∗P < 0.01; ∗∗∗P < 0.001. Uncropped images of blots are shown in Supplementary Fig. 8. Statistics source data for Supplementary Fig. 6f, g can be found in Supplementary Table 1.
Supplementary Figure 7 HSF1-JNK interactions regulate liver growth and proliferation, related to Fig. 8.
(a) and (b) Liver weights and lean mass of 6-week-old female mice were measured (mean ± s.d., n = number of mice per genotype shown in the graphs, One-way ANOVA). (c) Quantitation of mTORC1 signalling in mouse liver tissues shown in Fig. 7e (mean ± s.d., n = 3 independent experiments, One-way ANOVA). (d) Representative flow cytometry dot plots of co-stained liver cells with PI and anti-BrdU antibodies. (e) and (f) MCM2 and c-MYC levels were detected in mouse liver tissues by immunoblotting. (g) Caspase 3 activities were quantitated in liver tissues of 6-week-old male mice using DEVD-R110 as the substrate (mean ± s.d., n = 3 mice per genotype, One-way ANOVA). This experiment was repeated twice. (h) Hepatocyte-specific deletion of Hsf1 was verified by immunostaining of frozen sections of mouse liver tissues using rat monoclonal anti-HSF1 antibody cocktail (1:100) and CF594 anti-rat IgG secondary antibody conjugates. Arrows indicate hepatocytes and arrowheads indicate non-parenchymal cells. Of note, HSF1 expression was still detected in non-parenchymal cells following Cre-mediated recombination. Scale bars: 50 μm. Representative images from 2 independent experiments. (i) HgfmRNA levels were quantitated by qRT-PCR in primary Jnk1MEFs (mean of 3 wells of cells per genotype per experiment, and this experiment was repeated twice). (j) Hsp mRNA levels were quantitated by qRT-PCR in primary Jnk1 MEFs (mean, of 3 wells of cells per genotype per experiment, and this experiment was repeated twice). (k) HgfmRNA levels were quantitated by qRT-PCR in mouse liver tissues (mean ± s.d., n = 3 mice per genotype, One-way ANOVA). This experiment was repeated twice. (l) and (m) Phosphorylation of c-MET was detected by immunoblotting in mouse liver tissues. Statistical significance: ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001; n.s.: not significant. Uncropped images of blots are shown in Supplementary Fig. 8. Statistics source data for Supplementary Fig. 7c, g, i–k can be found in Supplementary Table 1.
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Su, KH., Cao, J., Tang, Z. et al. HSF1 critically attunes proteotoxic stress sensing by mTORC1 to combat stress and promote growth. Nat Cell Biol 18, 527–539 (2016). https://doi.org/10.1038/ncb3335
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DOI: https://doi.org/10.1038/ncb3335
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