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A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol

Nature volume 519, pages 370–373 (2015)Cite this article

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Abstract

Resveratrol is reported to extend lifespan1,2 and provide cardio-neuro-protective3, anti-diabetic4, and anti-cancer effects3,5 by initiating a stress response2 that induces survival genes. Because human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions6, we considered the possibility that the tyrosine-like phenolic ring of resveratrol might fit into the active site pocket to effect a nuclear role. Here we present a 2.1 Å co-crystal structure of resveratrol bound to the active site of TyrRS. Resveratrol nullifies the catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD+-dependent auto-poly-ADP-ribosylation of poly(ADP-ribose) polymerase 1 (PARP1). Downstream activation of key stress signalling pathways are causally connected to TyrRS–PARP1–NAD+ collaboration. This collaboration is also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analogue. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites7, here a non-spliced TyrRS catalytic null reveals a new PARP1- and NAD+-dependent dimension to the physiological mechanism of resveratrol.

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Figure 1: Resveratrol binds at the active site of TyrRS.
Figure 2: TyrRS facilitates the activation of PARP1 in an active-site-dependent manner.
Figure 3: Resveratrol and serum starvation mimic similar downstream signalling events mediated by PARP1 activation.
Figure 4: Resveratrol treatment activates TyrRS–PARP1-driven signalling events in mouse tissues.

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Protein Data Bank

Data deposits

X-ray structure coordinates of resveratrol-bound TyrRS and l-Tyr bound TyrRS have been deposited in Protein Data Bank under accession numbers 4Q93 and 4QBT, respectively.

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Acknowledgements

This work was supported in part the National Cancer Institute grant CA92577, by a fellowship from the National Foundation for Cancer Research, and by aTyr Pharma through an agreement with The Scripps Research Institute. We thank the The Scripps Research Institute mouse facility for their efforts for this project. We also thank P. Chang for the ZZ-PARP1 clone, and the PARG and PARG-MT proteins, and Y. Shi for independently repeating some of the key experiments. We thank P. Chang, J. H. Chung, L. Guarente, L. Krauss, D. Sinclair, and C. Westphal for comments and suggestions on this work.

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Authors and Affiliations

  1. Department of Molecular and Cell Biology, The Skaggs Institute for Chemical Biology, The Scripps Laboratories for tRNA Synthetase Research, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA,

    Mathew Sajish & Paul Schimmel

  2. The Scripps Florida Research Institute, 130 Scripps Way, Jupiter, 33458, Florida, USA

    Paul Schimmel

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  1. Mathew Sajish
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Contributions

M.S. and P.S. conceived the idea, designed the research, analysed the data, and wrote the manuscript. M.S. performed the experiments.

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Correspondence to Paul Schimmel.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Resveratrol inhibits TyrRS activation.

a, The ATP–PPi exchange assay as described in Methods demonstrated the inhibitory effect of resveratrol on TyrRS and b resveratrol shifts the Michaelis constant (Km) for tyrosine. c, Resveratrol binds TyrRS better than tyrosine. The apparent Ki for resveratrol was deduced by varying the concentration of RSV and plotting the slope of (1/v versus 1/[Tyr]) versus [RSV] as indicated.

Extended Data Figure 2 Resveratrol induces a distinct conformational change upon binding to active site of TyrRS.

a, Comparison of the overall conformational change induced by resveratrol at the active site of TyrRS by structure-based superposition (yellow, tyrosine-bound structure; magenta, resveratrol-bound structure). Note the conformational change near the helix region (P331–P342) that connects the linker region with the C-domain. b, Illustration of the extensive interactions of resveratrol with the active site. c, The trans-resveratrol (dark blue) docks (manual) into TyrRS active site without significant structural disturbances. d, Generation of a new pocket through a RSV-induced conformational change in TyrRS accommodates the dihydroxy phenolic ring of RSV (otherwise exposed to the destabilizing aqueous environment in the trans form) and hence facilitates the trans (dark blue) to cis (light blue) conversion of RSV.

Extended Data Figure 3 Resveratrol facilitates the TyrRS–PARP1 interaction in an active-site-dependent manner.

a, Both heat shock (42 °C for 30 min) and tunicamycin-treatment (10 μg ml−1, endoplasmic reticulum stress) facilitated the nuclear translocation of TyrRS and activation of PARP1. b, Resveratrol or serum starvation facilitate TyrRS interaction with PARP1, and Tyr-SA prevents this interaction. ZZ-PARP1 was immunoprecipiated with IgG from HeLa cells treated with RSV or serum starvation alone or in combination with Tyr-SA. c, Resveratrol- or serum-starvation-mediated PARP1 activation is blocked only by Tyr-SA and not by Gly-SA. d, TyrRS interacts directly with PARP1. HeLa cell lysate after RSV treatment (5 μM, 30 min) was divided into three parts and treated with PARG and catalytically inactive PARG-MT. PARP1 was immunoprecipitated and analysed for TyrRS interaction. e, Model illustrating the mechanism of RSV-mediated TyrRS interaction with PARP1 and subsequent release after auto-PARylation. f, Ni-NTA pull-down of N- and C-terminal fragments of PARP1 overexpressed in E. coli demonstrates that TyrRS interacts with the C-terminal region of PARP1. g, Only the full-length TyrRS (1–528), but none of the various fragments of TyrRS (mini-TyrRS (1–364), ΔN-TyrRS (228–528), or the C-domain (328–528)), interacts with PARP1. h, Coomassie blue staining of a gel showing the total protein input in for the experiment of Extended Data Fig. 3g.

Extended Data Figure 4 Tyrosyl-AMP analogue (Tyr-SA) does not affect DNA-dependent auto-PARylation of PARP1.

a, Silver-stained SDS–PAGE gel showing the purity and input of PARP1 and TyrRS in the in vitro PARylation study of Fig. 2. b, Quantitation (Image J software) of the band intensity of PARylated PARP1 in Fig. 2a, top. c, Tyrosyl-AMP analogue (Tyr-SA) does not affect DNA-dependent auto-PARylation of PARP1. d, Overexpression of nuclear-translocation-weakened mutant of TyrRS6 is less effective in activating PARP1. e, Y314A-TyrRS is more sensitive to RSV than is TyrRS in facilitating PARP1 activation.

Extended Data Figure 5 Resveratrol enhances the acetylation of Tip60 and modulates NAD+ concentration in a dose- and time-dependent manner.

a, Treatment of HeLa cells (1 h) with increasing concentration of resveratrol enhances the acetylation level of Tip60. Activation of Tip60 was monitored by histone acetylation status. b, Total NAD+ contents of serum-starved cells or RSV-treated samples were compared with untreated samples at 15 min using a commercially available BioVision NAD+/NADH quantitation colorimetric kit. c, Total nicotinamide or ADP-ribose produced was deduced from the difference in the amount of NAD+ in each sample with respect to the untreated sample (consumption of one mole of NAD+ would give rise one mole of nicotinamide and one mole of ADP-ribose). d, Total NAD+ content of the serum-starved cells or RSV-treated samples were compared with untreated samples at 1 h. (Although the experiments were done in biological triplicates (all samples showing similar results), the error bars in the figure represent the deviations from the mean of the technical triplicates from one representative biological sample.) e, f, Time course study of poly-ADP-ribosylation status and associated signalling events after (e) serum starvation (extended time course data of the same image shown in Fig. 3c) and (f) treatment with 5 μM RSV. Using the respective antibodies, Activation of p53 was monitored by the induction of p21 and SIRT6. Activation of NRF2 was monitored by HO-1 induction.

Extended Data Figure 6 siRNA (siRNATyrRS or siRNAPARP1), with and without low RSV (5 μM), does not affect cell viability.

HeLa cells (1 × 106) were reverse-transfected with siRNA targeted to TyrRS or PARP1. An siRNACon (a scrambled sequence of siRNAPARP1) was used as a control. Viability was monitored using the RTCA iCELLigence System (ACEA Biosciences). Samples were treated with RSV (5 μM) at 60 h and monitoring was continued for another 2 h for siRNATyrRS (a total of 62 h of monitoring) and for another 16 h for siRNACon and siRNAPARP1 (total 76 h monitoring).

Extended Data Figure 7 siRNASIRT1 did not affect downstream signalling events at low RSV (5 μM).

HeLa cells were treated with siRNASIRT1 for 60 h to knockdown SIRT1. HeLa cells were treated with RSV (5 μM) for another 4 h and samples were collected intervals as indicated. Samples were analysed for downstream signalling markers using appropriate antibodies.

Extended Data Figure 8 siRNA- (siRNATyrRS or siRNAPARP1) treated cells did not upregulate the levels of NAD+ in response to RSV (5 μM) after 1 h.

HeLa cells (1 × 106) were reverse transfected, separately, with siRNA targeted to PARP1 or TyrRS. A scrambled sequence of target siRNA was used as a control. The total NAD+ content of RSV (5 μM)-treated samples was compared with untreated samples at 1 h, using a commercially available BioVision NAD+/NADH quantitation colorimetric kit. (Although the experiments were done in biological triplicates (all samples showing similar results), the error bars in the figure represent the deviations from the mean of the technical triplicates from one representative biological sample.) The comparator (shown as a dashed bar) is taken from Extended Data Fig. 5d.

Extended Data Figure 9 Resveratrol treatment activates PARP1 and associated signalling events in the mouse tissues.

a, Activation of PARP1 in mouse muscle tissue treated with resveratrol monitored by increased PARylation and b by increased acetylation status. Activations of Tip60 and AMPK were monitored by using α-AcK16-H4 and α-pSer36-H2B, respectively. c, Activation of PARP1 in mouse heart tissue treated with resveratrol monitored by increased PARylation and d by increased acetylation status. e, Resveratrol treatment causes only a transient activation on PARP1. Immunoblotting of mouse muscle tissue samples after 24 h of RSV treatment showed no significant difference in the level of PARP1PAR compared with control. f, RSV treatment enhances TyrRS interaction with and activation of PARP1 in the muscle tissue. g and h, Resveratrol-mediated activation of PARP1 (g, monitored by PARylation status; h, monitored by acetylation status) is blocked by Tyr-SA in mouse heart tissues.

Extended Data Table 1 Data collection and refinement statistics
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Sajish, M., Schimmel, P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 519, 370–373 (2015). https://doi.org/10.1038/nature14028

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