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The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress

Abstract

Organisms respond to mitochondrial stress by activating multiple defense pathways, including the mitochondrial unfolded protein response (UPRmt). However, how UPRmt regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here, we identify CREB-binding protein-1 (CBP-1), the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPRmt, as well as the mitochondrial stress-induced immune response, with involvement also in the reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of the histone demethylases JMJD-1.2 and JMJD-3.1 and upstream of UPRmt transcription factors, including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts the UPRmt in mammalian cells, while forced expression of p300 is sufficient to activate it. These results highlight an evolutionarily conserved mechanism that determines the mitochondrial stress response and promotes health and longevity through CBP/p300.

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Fig. 1: CBP-1 controls activation of the UPRmt in C. elegans.
Fig. 2: Mitochondrial stress increases CBP-1-dependent histone acetylation at the loci of a large set of UPRmt genes.
Fig. 3: CBP-1 acts downstream of JMJD-3.1/JMJD-1.2 and upstream of ATFS-1 to support the expression of UPRmt genes.
Fig. 4: CBP-1 is essential for mitochondrial surveillance, MSR-associated immune response, lifespan extension and Aβ proteotoxicity reduction.
Fig. 5: Expression of CBP/p300 positively correlates with UPRmt transcripts and longevity in mouse and human populations.
Fig. 6: Functions of CBP/p300 in UPRmt activation are conserved in mammals.
Fig. 7: Model for CBP-1- or CBP/p300-mediated regulation of MSR and longevity.

Data availability

The RNA/DNA sequencing datasets have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus database with the accession numbers GSE131611 (for worm RNA-seq), GSE148328 (for worm ChIP-seq), GSE131613 (for MEF RNA-seq) and GSE156830 (for human HepG2 RNA-seq). Functional clustering in this study was performed using the Database for Annotation, Visualization and Integrated Discovery, version 6.8 (https://david.ncifcrf.gov/home.jsp). The BXD, LXS and GTEx transcriptome datasets used in this study are available from the GeneNetwork database (https://www.genenetwork.org). All data supporting the findings of this study are available from the corresponding author upon request. Source data are provided with this paper.

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Acknowledgements

We thank the Caenorhabditis Genetics Center for providing the C. elegans strains. We thank P. K. Brindle for providing the CBP/p300−/− MEFs. We thank all members of the J. Auwerx and K. Schoonjans laboratories for helpful discussions. This work was supported by grants from the École Polytechnique Fédérale de Lausanne, European Research Council (ERC-AdG-787702) and Swiss National Science Foundation (31003A_179435) and a Global Research Laboratory grant from the National Research Foundation of Korea (2017K1A1A2013124). T.Y.L. was supported by the Human Frontier Science Program (LT000731/2018-L). L.J.E.G. is supported by a Swiss Government Excellence Scholarship (FCS ESKAS-Nr. 2019.0009).

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Contributions

T.Y.L. and J.A. conceived of the project. T.Y.L. performed most of the experiments. A.W.G. contributed to the C. elegans lifespan experiments. A.M. contributed to the P. aeruginosa infection experiment. T.Y.L., M.B.S., H.L., A.M.B., G.E.A., X.L. and L.J.E.G. performed the data analysis. K.S. and J.A. supervised the study. T.Y.L. and J.A. wrote the manuscript with comments from all authors.

Corresponding author

Correspondence to Johan Auwerx.

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Extended data

Extended Data Fig. 1 Inhibition of CBP-1 by RNAi or pharmacological inhibitors attenuates UPRmt activation in C. elegans.

a, All putative lysine acetyltransferases (KATs) in C. elegans and their human homologues. The worm KATs were validated/identified by searching the C. elegans protein database for proteins with a conserved acetyltransferase domain, and high amino acid sequences identities of the known human KATs30. b, Role of KATs in UPRmt activation in C. elegans. hsp-6p::gfp worms were fed with control (ev) or cco-1 (40%) RNAi in combination with RNAi targeting different KATs (60%). c, d, cbp-1 RNAi attenuates the UPRmt activation induced by cco-1 (c) or mrps-5 (d) RNAi in a dose-dependent manner. RNAi targeting cco-1 or mrps-5 occupied 40%. cbp-1 RNAi occupied 10-60%. Control RNAi was used to supply to a final 100% of RNAi for all conditions. e, Schematic diagram showing the different regions regulated by the two different cbp-1 RNAi, and the two CBP/p300 inhibitors (PF-CBP1 and A-485). KIX, kinase-inducible domain interacting domain; Br, bromodomain; HAT, histone acetyltransferase domain; a.a., amino acids; n.t., nucleotides. f, The alternative cbp-1 RNAi (cbp-1_2) also inhibits UPRmt activation. RNAi targeting mrps-5 or spg-7 occupies 40%, cbp-1 RNAi occupies 25%. g, A-485 attenuates UPRmt activation induced by mrps-5 RNAi in a dose-dependent manner. hsp-6p::gfp worms were fed with control or mrps-5 RNAi (40%), in combination with 0-20 μM A-485. h, i, RNAi that specifically targets cbp-2 or cbp-3 failed to abolish UPRmt activation in hsp-6p::gfp worms. Photos (h) and qRT-PCR-results (n = 4 biologically independent samples) (i) of hsp-6p::gfp worms fed with control, cco-1 (40%), cbp-1 (25%), cbp-2 (Ahringer library) or cbp-3 RNAi. Error bars denote SEM. Statistical analysis was performed by two-tailed unpaired Student’s t-test. j, Schematic diagram showing the protein structure of CBP-1, CBP-2 and CBP-3. The numbers in red indicate the amino acid sequence identities between two proteins in comparison. km, cbp-1 RNAi attenuates the UPRER activation induced by tunicamycin (5 μg/ml) (k), hsp-3 (l) or enpl-1 (m) RNAi in hsp-4p::gfp worms. RNAi targeting hsp-3 or enpl-1 occupies 40%, cbp-1 RNAi occupies 25%, atfs-1 RNAi occupies 60%. n, cbp-1 RNAi does not affect the cytosolic UPR (UPRCYT)/heat shock response activation induced by heat shock. hsp16.2p::gfp reporter worms were fed with different percentages of cbp-1 RNAi as indicated. As positive control, heat shock for 8 h at 31 °C could induce the UPRCYT and cbp-1 RNAi did not block this response. Scale bars, 0.3 mm.

Extended Data Fig. 2 UPRmt genes dependent or independent of CBP-1 and ATFS-1 for expression.

a, Principal-component analysis (PCA) of the RNA-seq profiles of worms treated with the indicated RNAi. b, Diagram of genes up-regulated after cco-1 RNAi, in common with genes up-regulated after mrps-5 RNAi according to the RNA-seq data. cf, qRT-PCR-results of indicated genes in hsp-6p::gfp worms fed with control (ev), cco-1, mrps-5, cbp-1 or atfs-1 RNAi (n = 4 biologically independent samples). RNAi targeting cco-1 or mrps-5 occupies 50%, cbp-1 occupies 25%, atfs-1 occupies 50%. g, qRT-PCR-results of hsp-6p::gfp worms fed with control (ev), spg-7, timm-23, tomm-40, cts-1 or dlst-1 RNAi (n = 4 biologically independent samples). UPRmt genes dependent on both CBP-1 and ATFS-1 for induction according to the RNA-seq dataset (as summarized in Fig. 1g) are highlighted in red. Genes only dependent on CBP-1, but not ATFS-1, are highlighted in blue. h, Diagram of the down-regulated genes after single cco-1 RNAi (orange), in common with down-regulated (blue) or up-regulated (pink) genes after single cbp-1 RNAi according to the RNA-seq data. i, j, Functional clustering of the 709 (i) and 190 (j) genes as indicated in (h). k, Diagram of genes down-regulated after cco-1 RNAi, in common with genes down-regulated after mrps-5 RNAi according to the RNA-seq data. Error bars denote SEM. Statistical analysis was performed by ANOVA followed by Tukey post-hoc test.

Extended Data Fig. 3 Mitochondrial stress increases CBP-1-mediated histone acetylation at the loci of UPRmt, but not UPRER or UPRCYT genes.

a, Western blots of hsp-6p::gfp worms fed with control, cbp-1, atfs-1, cco-1 or mrps-5 RNAi. RNAi targeting cbp-1 occupies 25%, atfs-1, cco-1 or mrps-5 occupies 50%. b-e, Genome tracks showing the ChIP-seq analysis for H3K27Ac and H3K18Ac over the genomic loci of gpd-2 (b), hsp-3 (c), hsp-4 (d) and hsp-16.2 (e) in worms fed with control or cco-1 RNAi. The two tracks were shown with the same total count range between basal and mitochondrial stress condition for each gene. f, Summary of the distribution analysis of the 265 increased H3K18Ac/H3K27Ac peaks on the 134 UPRmt genes (as indicated in Fig. 2d) in response to mitochondrial stress. For uncropped gel source data, see Source Extended Data Fig. 3.

Source data

Extended Data Fig. 4 RNAi of cbp-1 caused a severe developmental delay in the worm Alzheimer’s disease model GMC101, but not in the control CL2122 strain.

Representative photos of CL2122 or GMC101 worms fed with control or cbp-1 (10% or 20%) RNAi since maternal L4 stage. The developmental stage and body length of the F1 progeny were quantified at Day 4 after hatching (n = 25 worms for each condition). Conditions with 20% cbp-1 RNAi were not quantified as most of the eggs failed to hatch in GMC101 worms fed with 20% cbp-1 RNAi. Scale bar, 1 mm. Error bars denote SEM. Statistical analysis was performed by ANOVA followed by Tukey post-hoc test.

Extended Data Fig. 5 CBP/p300 expression positively correlates with Kdm6b/Phf8, UPRmt transcripts and lifespan in mouse populations.

a, Pearson’s correlation co-expression heat-map for CBP/p300, Kdm6b/Phf8 and UPRmt genes in hippocampus and hypothalamus of the BXD mouse genetic reference population43,52. Positive and negative correlations are indicated in red and blue, respectively. The intensity of the colors corresponds to correlation coefficients. b, Pearson’s correlation co-expression heat-map for CBP/p300, Kdm6b/Phf8 and UPRmt genes in the brain (whole brain) and prefrontal cortex of the LXS mouse genetic reference population53. c, Positive correlations between lifespan and CBP or p300 transcript levels in hippocampus and hypothalamus of BXD mice (Pearson’s r, two-sided). Each dot indicates an independent BXD strain.

Extended Data Fig. 6 An essential role of CBP/p300 and CBP/p300 acetyltransferase activity in UPRmt activation in mammalian cells.

a, Multidimensional scaling (MDS) plot of the RNA-seq profiles of wild-type (WT) and CBP/p300−/− MEFs treated with or without Dox (30 μg/ml) for 24 h. Note the decreased distance between Dox-treated and un-treated condition in the CBP/p300−/− background compared to that in WT background. b, CBP/p300−/− MEFs are insensitive to the treatment of mitochondrial stress inducer Dox. Volcano plots showing the effect of Dox treatment in wild-type (WT) (left) or CBP/p300−/− (right) MEFs on gene expression. FC, fold change. Genes that were up-regulated (log2FC > 0.5, adjusted P < 0.05) during Dox treatment were highlighted in red. Genes that were down-regulated (log2FC < -0.5, adjusted P < 0.05) were highlighted in blue. c, Heat-map of the representative UPRmt genes dependent on CBP/p300 for induction in response to Dox treatment in WT and CBP/p300−/− (KO) MEFs, according to the RNA-seq data. The heat-map was shown in log2FC values. d, MDS plot of the RNA-seq profiles of HepG2 cells treated with or without CBP/p300 acetyltransferase activity inhibitor A-485 (5 μM) and/or Dox (30 μg/ml) for 24 h. e, The CBP/p300 catalytic inhibitor A-485 attenuates the effect of Dox on gene expression in HepG2 cells. Volcano plots showing the effect of Dox on gene expression of HepG2 cells in control (DMSO) (left) or A-485 (right) treatment background. FC, fold change. Genes that were up-regulated (log2FC > 0.5, adjusted P < 0.05) during Dox treatment were highlighted in red. Genes that were down-regulated (log2FC < -0.5, adjusted P < 0.05) were highlighted in blue. f, Diagram of the UPRmt genes that are dependent (orange) or independent (grey) on CBP/p300 activity in response to Dox treatment in HepG2 cells, according to the RNA-seq data with A-485.

Extended Data Fig. 7 ATFS-1 can be acetylated by CBP-1 and affected by both class I/II and class III HDACs.

a, ATFS-1 was acetylated by CBP-1 in vivo. Flag-tagged ATFS-1 was expressed with or without CBP-1 acetyltransferase domain (CBP-1-HAT) in HEK293T cells, immunoprecipitated with anti-Flag antibody and analyzed by western blots. TCL, total cell lysate. b, ATFS-1 was acetylated by CBP-1 in vitro. Bacterially expressed GST tagged CBP-1-HAT was incubated with Flag-ATFS-1 with or without acetyl-CoA (Ac-CoA) and immunoblotted as indicated. c, Schematic diagram showing the protein structure of ATFS-1 and the acetylated sites identified by mass spectrometry. MTS, mitochondrial targeting sequence; SRR, Serine-rich region; NLS, Nuclear localization signal; LZD, Leucine zipper domain. d, HEK293T cells transfected as indicated were treated with or without TSA (class I/II HDAC inhibitor), or NAM (class III HDAC inhibitor) 8 h before harvesting, and analyzed by western blots. For uncropped gel source data, see Source Extended Data Fig. 7.

Source data

Supplementary information

Supplementary Information

Supplementary Table 7. List of primers used in this study for RT–qPCR and ChIP–qPCR.

Reporting Summary

Supplementary Table 1

RNA-seq results for worms fed with cco-1, mrps-5, cbp-1 or atfs-1 RNAi.

Supplementary Table 2

Impact of cbp-1 RNAi on the expression of downregulated genes after cco-1 RNAi.

Supplementary Table 3

H3K18Ac and H3K27Ac ChIP-seq results of worms fed with control or cco-1 RNAi.

Supplementary Table 4

Jmjd-3.1 and jmjd-1.2 overexpression-induced UPRmt genes that were also regulated by CBP-1.

Supplementary Table 5

RNA-seq results for wild-type and CBP/p300 knockout MEFs treated with or without Dox.

Supplementary Table 6

RNA-seq results for HepG2 cells treated with or without the CBP/p300 inhibitor A-485 and/or Dox.

Source data

Source Data Fig. 2

Uncropped western blots with size marker indications.

Source Data Fig. 3

Uncropped western blots with size marker indications.

Source Data Fig. 4

Uncropped western blots with size marker indications.

Source Data Fig. 6

Uncropped western blots with size marker indications.

Source Data Extended Data Fig. 3

Uncropped western blots with size marker indications.

Source Data Extended Data Fig. 7

Uncropped western blots with size marker indications.

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Li, T.Y., Sleiman, M.B., Li, H. et al. The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress. Nat Aging 1, 165–178 (2021). https://doi.org/10.1038/s43587-020-00025-z

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