Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation

An Erratum to this article was published on 25 June 2014

This article has been updated


Lymphocyte functions triggered by antigen recognition and co-stimulation signals are associated with a rapid and intense cell division, and hence with metabolism adaptation1. The nucleotide cytidine 5′ triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids2,3,4. CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases (or synthetases) 1 and 2 (CTPS1 with CTPS2); the respective roles of these two enzymes are not known5,6,7. CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes8,9. Here we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans that causes a novel and life-threatening immunodeficiency, characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were only weakly affected by the absence of CTPS1. Activated CTPS1-deficient cells had decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine. CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response. CTPS1 may therefore represent a therapeutic target of immunosuppressive drugs that could specifically dampen lymphocyte activation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Identification of CTPS1 deficiency in patients with a combined immunodeficiency.
Figure 2: Induction of CTPS1 expression during T-cell activation and defective proliferation of activated CTPS1-deficient T cells.
Figure 3: CTPS1 is required for proliferation of T cells in response to TCR-CD3 activation.

Similar content being viewed by others

Change history

  • 25 June 2014

    Nature 510, 288–292 (2014); doi:10.1038/nature13386 Owing to a production error, the vertical axis of the right panel of Fig. 3g was misaligned. The correct panel is shown below as Fig. 1 of this Erratum. In addition, the legends for Fig. 2 and Extended Data Fig. 3 should read “Induction of CTPS1 expression during T- and B-cell activation and defective proliferation of activated CTPS1-deficient T and B cells” and “Induction of CTPS1 expression in activated B cells and inhibitors of CTPS1 expression in activated T cells”, respectively.


  1. MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259–283 (2013)

    Article  CAS  Google Scholar 

  2. Evans, D. R. & Guy, H. I. Mammalian pyrimidine biosynthesis: fresh insights into an ancient pathway. J. Biol. Chem. 279, 33035–33038 (2004)

    Article  CAS  Google Scholar 

  3. Higgins, M. J., Graves, P. R. & Graves, L. M. Regulation of human cytidine triphosphate synthetase 1 by glycogen synthase kinase 3. J. Biol. Chem. 282, 29493–29503 (2007)

    Article  CAS  Google Scholar 

  4. Ostrander, D. B., O’Brien, D. J., Gorman, J. A. & Carman, G. M. Effect of CTP synthetase regulation by CTP on phospholipid synthesis in Saccharomyces cerevisiae. J. Biol. Chem. 273, 18992–19001 (1998)

    Article  CAS  Google Scholar 

  5. Kassel, K. M., Au D. R, Higgins M. J, Hines, M. & Graves, L. M. Regulation of human cytidine triphosphate synthetase 2 by phosphorylation. J. Biol. Chem. 285, 33727–33736 (2010)

    Article  CAS  Google Scholar 

  6. Nadkarni, A. K. et al. Differential biochemical regulation of the URA7- and URA8-encoded CTP synthetases from Saccharomyces cerevisiae. J. Biol. Chem. 270, 24982–24988 (1995)

    Article  CAS  Google Scholar 

  7. van Kuilenburg, A. B., Meinsma, R., Vreken, P., Waterham, H. R. & van Gennip, A. H. Identification of a cDNA encoding an isoform of human CTP synthetase. Biochim. Biophys. Acta 1492, 548–552 (2000)

    Article  CAS  Google Scholar 

  8. Fairbanks, L. D., Bofill, M., Ruckemann, K. & Simmonds, H. A. Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans. Disproportionate expansion of pyrimidine pools and contrasting effects of de novo synthesis inhibitors. J. Biol. Chem. 270, 29682–29689 (1995)

    Article  CAS  Google Scholar 

  9. van den Berg, A. A. et al. Cytidine triphosphate (CTP) synthetase activity during cell cycle progression in normal and malignant T-lymphocytic cells. Eur. J. Cancer 31, 108–112 (1995)

    Article  Google Scholar 

  10. Wynn, R. F. et al. Treatment of Epstein-Barr-virus-associated primary CNS B cell lymphoma with allogeneic T-cell immunotherapy and stem-cell transplantation. Lancet Oncol. 6, 344–346 (2005)

    Article  Google Scholar 

  11. Notarangelo, L. D. Functional T cell immunodeficiencies (with T cells present). Annu. Rev. Immunol. 31, 195–225 (2013)

    Article  CAS  Google Scholar 

  12. Kursula, P. et al. Structure of the synthetase domain of human CTP synthetase, a target for anticancer therapy. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 62, 613–617 (2006)

    Article  CAS  Google Scholar 

  13. Traut, T. W. Physiological concentrations of purines and pyrimidines. Mol. Cell. Biochem. 140, 1–22 (1994)

    Article  CAS  Google Scholar 

  14. Ben-Sahra, I., Howell, J. J., Asara, J. M. & Manning, B. D. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339, 1323–1328 (2013)

    Article  ADS  CAS  Google Scholar 

  15. McPartland, R. P., Wang, M. C., Bloch, A. & Weinfeld, H. Cytidine 5′-triphosphate synthetase as a target for inhibition by the antitumor agent 3-deazauridine. Cancer Res. 34, 3107–3111 (1974)

    CAS  PubMed  Google Scholar 

  16. Qiu, Y. et al. Mycophenolic acid-induced GTP depletion also affects ATP and pyrimidine synthesis in mitogen-stimulated primary human T-lymphocytes. Transplantation 69, 890–897 (2000)

    Article  CAS  Google Scholar 

  17. van den Berg, A. A. et al. The roles of uridine-cytidine kinase and CTP synthetase in the synthesis of CTP in malignant human T-lymphocytic cells. Leukemia 8, 1375–1378 (1994)

    CAS  PubMed  Google Scholar 

  18. Le Bourhis, L., Mburu, Y. K. & Lantz, O. MAIT cells, surveyors of a new class of antigen: development and functions. Curr. Opin. Immunol. 25, 174–180 (2013)

    Article  CAS  Google Scholar 

  19. Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nature Immunol. 9, 503–510 (2008)

    Article  CAS  Google Scholar 

  20. Chung, B. K. et al. Innate immune control of EBV-infected B cells by invariant natural killer T cells. Blood 122, 2600–2608 (2013)

    Article  CAS  Google Scholar 

  21. Brennan, P. J., Brigl, M. & Brenner, M. B. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nature Rev. Immunol. 13, 101–117 (2013)

    Article  CAS  Google Scholar 

  22. Toy, G. et al. Requirement for deoxycytidine kinase in T and B lymphocyte development. Proc. Natl Acad. Sci. USA 107, 5551–5556 (2010)

    Article  ADS  CAS  Google Scholar 

  23. Marijnen, Y. M. et al. Studies on the incorporation of precursors into purine and pyrimidine nucleotides via ‘de novo’ and ‘salvage’ pathways in normal lymphocytes and lymphoblastic cell-line cells. Biochim. Biophys. Acta 1012, 148–155 (1989)

    Article  CAS  Google Scholar 

  24. Austin, W. R. et al. Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress. J. Exp. Med. 209, 2215–2228 (2012)

    Article  CAS  Google Scholar 

  25. Murali-Krishna, K. et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998)

    Article  CAS  Google Scholar 

  26. Hislop, A. D., Taylor, G. S., Sauce, D. & Rickinson, A. B. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu. Rev. Immunol. 25, 587–617 (2007)

    Article  CAS  Google Scholar 

  27. Huang, M. & Graves, L. M. De novo synthesis of pyrimidine nucleotides; emerging interfaces with signal transduction pathways. Cell. Mol. Life Sci. 60, 321–336 (2003)

    Article  CAS  Google Scholar 

  28. Robitaille, A. M. et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339, 1320–1323 (2013)

    Article  ADS  CAS  Google Scholar 

  29. Gülow, K. et al. HIV-1 trans-activator of transcription substitutes for oxidative signaling in activation-induced T cell death. J. Immunol. 174, 5249–5260 (2005)

    Article  Google Scholar 

  30. Latour, S. et al. Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nature Immunol. 2, 681–690 (2001)

    Article  CAS  Google Scholar 

  31. Picard, C. et al. Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity. Eur. J. Immunol. 39, 1966–1976 (2009)

    Article  CAS  Google Scholar 

  32. Luo, B., Groenke, K., Takors, R., Wandrey, C. & Oldiges, M. Simultaneous determination of multiple intracellular metabolites in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle by liquid chromatography-mass spectrometry. J Chromatogr. A 1147, 153–164 (2007)

    Article  CAS  Google Scholar 

  33. Scavennec, J., Maraninchi, D., Gastaut, J. A., Carcassone, Y. & Cailla, H. L. Purine and pyrimidine ribonucleoside monophosphate patterns of peripheral blood and bone marrow cells in human acute leukemias. Cancer Res. 42, 1326–1330 (1982)

    CAS  PubMed  Google Scholar 

Download references


The authors thank the patients, their families and the healthy donors for cooperation. We thank S. Rigaud, S. Gérart, C. Synaeve and R. Rodriguez for help with experiments and P. Revy for discussion. This work was supported by grants from INSERM, ANR (ANR-08-MIEN-012-01, ANR-2010-MIDI-005-02 and ANR-10-IAHU-01), Fondation ARC (France), the European Research Council (ERC-2009-AdG_20090506 n°FP7-249816) and the Rare Diseases Fondation (France). S. L. is a senior scientist of CNRS (France). E. M. is supported by ANR (France) and Ligue contre le cancer (France). We are also grateful to the UK 1958 Birth Cohort ( for providing DNA from 752 individuals born in the northwest of England. Access to these resources was enabled via the 58READIE Project funded by the Wellcome Trust and Medical Research Council (grant numbers WT095219MA and G1001799). A full list of the financial, institutional and personal contributions to the development of the 1958 Birth Cohort Biomedical resource is available at (

Author information

Authors and Affiliations



E.M. performed experiments, analysed the data and participated in the writing of the manuscript. N.P., F.H., C.L., S.F., C.M. and S.S. performed experiments. A.F., S.L., S.S., J.S., C.P., P.N., J.M., N.J., C.M. and N.T. analysed the data. M.D.E., R.F.W. and P.D.A. identified the families and provided and analysed clinical information. S.L. and A.F. co-wrote the manuscript. S.L. designed and supervised the research.

Corresponding author

Correspondence to Sylvain Latour.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Identification of a genetic CTPS1 defect in patients P1.1, P1.2 and P2.1.

a, Analysis of the single nucleotide variations (SNVs) detected by whole-exome sequencing in the genome of P1.1, P1.2 and P2.1. The numbers of SNVs are indicated in the triangles. SNVs were filtered by removal of non-functional intronic and synonymous mutations, heterozygous variations and those present in dbSNPs, 1000 genomes databases. The intersection of the filtered SNVs in the three patients resulted in the identification of a single common splicing site variation in the CTPS1 gene. b, Exon–intron structure and sequences of exons 17, 18 and 19 of CTPS1. The position of the variation is indicated by an arrow. The boxed nucleotide corresponds to the alternative splice site which produces a shorter transcript lacking exon 18 detected in patient cells. The alternative stop codon is indicated by an asterisk. c, Expression of a CTPS1 transcript lacking exon 18 (CTPS1Δ18) in CTPS1-deficient patients. The relative expression of full length CTPS1, CTPS1Δ18 and actin transcripts was examined by qRT–PCR in EBV-B cell lines (patient P2.1) and T-cell blasts (patient P1.2) from CTPS1-deficient patients. qRT–PCRs of actin are shown as normalization controls of the cDNA samples. Three fold-serial dilutions of cDNAs (indicated as 1, 0.3 and 0.1) were used for amplification of each transcript. Base pair markers are shown on the left. PCR products were verified by sequencing showing the expression of an abnormal CTPS1 transcript lacking exon 18 in the cells of the patients.

Extended Data Figure 2 Loss of CTPS1 expression and undetectable expression of the mutant CTPS1Δ18 protein in cells from CTPS1-deficient patients.

a, Transient expression of CTPS1 and the mutant CTPS1Δ18 in 293-T cells transfected with vectors containing wild-type CTPS1 or the mutant CTPS1Δ18. Cell lysates were tested by immunoblotting for CTPS1 with different antibodies raised against CTPS1 and for actin as a control for loading. The CTPS1Δ18 mutant protein is recognized by the rabbit polyclonal antibodies raised against the 341 to 355 (anti-341-355) or the 416 to 430 (anti-416-430) residues of CTPS1 but not by the rabbit polyclonal antibody K21. b, T-cell blasts from a healthy control (Ctr.) and the CTPS1-deficient patient P1.2 (P1.2) stimulated for 48 h with anti-CD3 were analysed for CTPS1 expression with the rabbit polyclonal antibodies anti-416-430 and anti-341-355. Actin expression as control for loading. c, EBV B-cell lines from healthy controls (Ctr. 1 and Ctr.2) and CTPS1-mutated patients (P1.2 and P2.1) were analysed for CTPS1 expression with the rabbit polyclonal antibody anti-416-430. Actin expression served as control for loading.

Extended Data Figure 3 Induction of CTPS1 expression in activated B cells.

a, Immunoblots for CTPS1 expression in sorted CD19+B cells (from PBMCs of an healthy donor) stimulated with the indicated stimuli. Actin was used as a loading control. b, Kinetics of CTPS1 mRNA expression monitored by qRT–PCR in sorted B cells that have been stimulated with anti-BCR+CpG. Expression is in arbitrary units (a.u.) normalized to the expression of the GADPH gene and leukocytes were used as calibrator. c, Immunoblots for CTPS1 expression in T-cell blasts (from an healthy donor) stimulated with anti-CD3/CD28 beads in the presence of selective inhibitors of NFκB, Src kinases, Ca2+, ERK kinase and PI3Kdelta. Actin was used as a loading control. The activity of the inhibitors was controlled in parallel (see Methods and data not shown).

Extended Data Figure 4 Analysis of proximal and late TCR activation responses in CTPS1-deficient cells.

a, Immunoblots showing the phosphorylation of proximal signalling molecules in T-cell blasts from a control donor (Ctr.) and a CTPS1-deficient patient P1.2 (P1.2) stimulated with anti-CD3 antibodies for 0, 2, 5, 15, 30 and 60 min or PMA plus ionomycin (P + I). Cell lysates were immunoblotted with antibodies against tyrosine-phosphorylated residues (PY), phosphoPLCG1 (pPLCG1), PLCG1, NFAT2c, phosphoPKCtheta (pPKCtheta), IkBa, phosphoERK1/2 (pERK1/2) and actin as a loading control. Molecular weights are on the left. Data correspond to one representative experiment of 2 or 3 independent experiments. b, Flow cytometry analyses of Ca2+-flux in T cells from PBMCs or T-cell blasts of a control donor (Ctr.) and a CTPS1-deficient patient P1.2 (P1.2) loaded with the Ca2+-sensitive fluorescent dye Indo-1. Cells were then stimulated with anti-CD3 antibodies (first arrow) crosslinked with rabbit anti-mouse antibodies (second arrow) and then incubated with ionomycin (third arrow) to induce a receptor-independent Ca2+ response. Intracellular Ca2+ levels are expressed in arbitrary units (a.u.). Data with the T-cell blasts correspond to one of three representative experiments. c, Analysis of the degranulation capacity of CD8+ T-cell blasts from two control donors (Ctr.1 and Ctr.2) and a CTPS1-deficient patient P1.2 (P1.2) stimulated with the indicated concentrations of anti-CD3 antibodies for 4 h. Cells were stained with antibodies against CD107a/b (LAMP1/2), a surface-exposed marker of the secretion of lytic granules, and then analysed by FACS. Means with s.d of percentages of CD8+ CD107+ cells are presented. d, Flow cytometry analysis of intracellular IL-2 production in CD4+ and CD8+ T cells from PBMCs of a control donor (Ctr.) and two CTPS1-deficient patients P1.2 and P2.2 (P1.2 and P2.2) stimulated for 36 h with anti-CD28 and anti-CD3 antibodies. The percentages of CD4+IL-2+ and CD8+IL-2+ are shown. e, Flow cytometry analysis of intracellular IFN-γ and TNF-α production on gated CD3+ T-cell blasts of a control donor (Ctr.) and a CTPS1-deficient patient P1.2 (P1.2) stimulated for 12 h with IL-2, anti-CD3 and anti-CD28 coated beads (anti-CD3/CD28), PMA plus ionomycin or PHA. Data are representative of one of 3 independent experiments. Dot-plots in red correspond to the isotype control. f, Induction of CD25 and CD69 in CD3+ T-cell blasts from a control donor (Ctr.) and a CTPS1-deficient patient (P1.2) was assessed after 24 h of anti-CD3 stimulation for CD69 and 96 h for CD25. Expression was assessed by flow cytometry and the median fluorescence intensity (MFI) is presented. Data are means with s.d of four and eight independent experiments for CD69 and CD25, respectively. Unpaired Student’s t-test. ***P < 0.001, *P < 0.05. g, Analysis of activation-induced cell death (AICD) in CD3+ T-cell blasts from a control donor (Ctr.) and a CTPS1-deficient patient P1.2 (P1.2,) after stimulation with the indicated concentration of anti-CD3 antibodies for 12 h. Apoptotic cells were detected by annexin V and 7-AAD staining and the percentages of annexin V positive/7-AAD negative cells within the gated CD3 population are shown. Data are means with s.d. of four (P1.2, n = 4) and eight (Ctr., n = 8) independent experiments. Unpaired Student’s t-tests and *P < 0.05.

Extended Data Figure 5 Decreased proliferation of TCR-stimulated T cells from patients P1.1, P1.2 and P2.2. and IL-2-expanded natural killer cells from patient P1.2.

a, Proliferation of CD3+ T cells from PBMCs of control donors (Ctr.) and CTPS1-deficient patients (P1.1, P1.2; left panels) or (P1.2, P2.2; right panels). Right panels and left panels correspond to 2 independent experiments. Cells were stimulated with immobilized anti-CD3 and soluble anti-CD28 antibodies during the course of 6 days. The proliferation was determined by dilution of CFSE staining analysed by flow cytometry. Histograms correspond to CFSE staining dilutions for which the number of cell divisions was indicated at the top of each peak. b, Proliferation of CD3+ T and CD16+CD56+ natural killer cells from PBMCs of a control donor (Ctr.) and a CTPS1-deficient patient (P1.2). Cells were stimulated with anti-CD3/CD28 coated beads for 3 days or IL-2 for 7 days. Representative dot plots showing cell divisions by dilution of the violet dye and expression of the activation marker CD69. Inserts with histograms showing the violet dye dilution with the number cell divisions indicated at the top of each peak.

Extended Data Figure 6 Decreased incorporation of thymidine, uridine, cytidine, leucine and asparte in CTPS1-deficient cells.

a, Incorporation of [3H]thymidine, [3H]uridine, [3H]cytidine and [3H]leucine as tracers of DNA, RNA and protein synthesis in PBMCs from a control healthy donor (Ctr.) and a CTPS1-deficient patient (P1.2) stimulated or not (no stim.) for 3 days with anti-CD3 or PHA and for 6 days with tetanus toxoid, candidin or tuberculin. The concentration of [3H]cytidine used in these experiments is under the value allowing the restoration of normal proliferation in CTPS1-deficient cells (also see Methods). Data are means with s.d of two independent experiments with triplicates. Unpaired Student’s t-tests and ***P < 0.001, **P < 0.01, *P < 0.05. b, c, Incorporation of [14C]aspartate and [3H]thymidine in PBMCs (b) or T-cell blasts (c) from a control healthy donor (Ctr.) and a CTPS1-deficient patient (P1.2) stimulated or not (no stim.) for 3 days with anti-CD3 or PHA. Data means with s.d of three independent samples.

Extended Data Figure 7 Decreased proliferation of Jurkat cells following shRNA-mediated CTPS1 downregulation.

a, Expression of CTPS1 in Jurkat cells transduced with lentiviral vectors containing two distinct CTPS1 shRNAs (Sh CTPS1 #1 or Sh CTPS1 #2) or a scrambled shRNA (Sh scramble). Cell lysates were analysed by immunoblotting for CTPS1, CTPS2 and actin protein expression. b, Proliferation of Jurkat cells, in which CTPS1 expression was silenced, was monitored as a function of the loss of GFP expression and compared with cells transduced with the scrambled shRNA. The percentages of GFP-positive cells were determined by flow cytometry at the indicated time points with ‘time 0’ corresponding to 48 h post-transduction.

Extended Data Figure 8 Measurements of nucleotide pools in CTPS1-deficient T cells and in B/EBV cell lines from patients.

a, Concentration of ATP, GTP, UTP and CTP in cell extracts of T-cell blasts stimulated with anti-CD3/CD28 coated beads or not (no stim.) from control healthy donors (Ctr.) or from patient P1.2. Control cells were treated or not with deazauridine for 24 h before and during stimulation or not. Representative data from 3 independent experiments. b, Same as in a with EBV B-cell lines from control healthy donors (Ctr.) and patients P1.1 (squares), P1.2 (circles) and P2.1 (triangles). For controls, each symbol corresponds to a different control cell line (from a different healthy donor). Representative data from two independent experiments with blinding during the measurements. Bars correspond to averages. Unpaired Student’s t-tests and *P < 0.05, **P < 0.01, ***P < 0.001. CTP data are also shown in Fig. 3g, h.

Extended Data Table 1 Immunological data of CTPS1-deficient patients
Extended Data Table 2 Immunological features of PBMCs from patient P1.2 at 8 and 9 years

Supplementary information

Supplementary Information

This file contains a Supplementary Table. (PDF 593 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martin, E., Palmic, N., Sanquer, S. et al. CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation. Nature 510, 288–292 (2014).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing