Skip to main content

Thank you for visiting nature.com. 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.

  • Review Article
  • Published:

Autophagosome biogenesis comes out of the black box

Nature Cell Biology volume 23, pages 450–456 (2021)Cite this article

Subjects

Abstract

Macroautophagic clearance of cytosolic materials entails the initiation, growth and closure of autophagosomes. Cargo triggers the assembly of a web of cargo receptors and core machinery. Autophagy-related protein 9 (ATG9) vesicles seed the growing autophagosomal membrane, which is supplied by de novo phospholipid synthesis, phospholipid transport via ATG2 proteins and lipid flipping by ATG9. Autophagosomes close via ESCRT complexes. Here, we review recent discoveries that illuminate the molecular mechanisms of autophagosome formation and discuss emerging questions in this rapidly developing field.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Overview of autophagosome formation.
Fig. 2: Autophagy initiation.
Fig. 3: Autophagosome growth.
Fig. 4: Autophagosome closure.

Similar content being viewed by others

References

  1. Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Levine, B. & Kroemer, G. Biological functions of autophagy genes: a disease perspective. Cell 176, 11–42 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lamb, C. A., Yoshimori, T. & Tooze, S. A.The autophagosome: origins unknown, biogenesis complex. Nat. Rev. Mol. Cell Biol. 14, 759–774 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Wen, X. & Klionsky, D. J. An overview of macroautophagy in yeast. J. Mol. Biol. 428, 1681–1699 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nakatogawa, H. Mechanisms governing autophagosome biogenesis. Nat. Rev. Mol. Cell Biol. 21, 439–458 (2020).

    Article  CAS  PubMed  Google Scholar 

  6. Melia, T. J., Lystad, A. H. & Simonsen, A. Autophagosome biogenesis: from membrane growth to closure. J. Cell Biol. 219, e202002085 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zachari, M. & Ganley, I. G. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 61, 585–596 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hurley, J. H. & Young, L. N. Mechanisms of autophagy initiation. Annu. Rev. Biochem. 86, 225–244 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hanada, T. et al. The Atg12–Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J. Biol. Chem. 282, 37298–37302 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Ichimura, Y. et al. A ubiquitin-like system mediates protein lipidation. Nature 408, 488–492 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Maeda, S., Otomo, C. & Otomo, T. The autophagic membrane tether ATG2A transfers lipids between membranes. eLife 8, e45777 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Osawa, T. et al. Atg2 mediates direct lipid transfer between membranes for autophagosome formation. Nat. Struct. Mol. Biol. 26, 281–288 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Valverde, D. P. et al. ATG2 transports lipids to promote autophagosome biogenesis. J. Cell Biol. 218, 1787–1798 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Maeda, S. et al. Structure, lipid scrambling activity and role in autophagosome formation of ATG9A. Nat. Struct. Mol. Biol. 27, 1194–1201 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Matoba, K. et al. Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion. Nat. Struct. Mol. Biol. 27, 1185–1193 (2020).

    Article  PubMed  Google Scholar 

  16. Birgisdottir, A. B., Lamark, T. & Johansen, T. The LIR motif—crucial for selective autophagy. J. Cell Sci. 126, 3237–3247 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Kirkin, V., McEwan, D. G., Novak, I. & Dikic, I. A role for ubiquitin in selective autophagy. Mol. Cell 34, 259–269 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Kirkin, V. & Rogov, V. V. A diversity of selective autophagy receptors determines the specificity of the autophagy pathway. Mol. Cell 76, 268–285 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Johansen, T. & Lamark, T. Selective autophagy mediated by autophagic adapter proteins. Autophagy 7, 279–296 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nguyen, T. N. et al. Atg8 family LC3/GABARAP proteins are crucial for autophagosome–lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation. J. Cell Biol. 215, 857–874 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tsuboyama, K. et al. The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. Science 354, 1036–1041 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Kim, J. et al. Cvt9/Gsa9 functions in sequestering selective cytosolic cargo destined for the vacuole. J. Cell Biol. 153, 381–396 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shintani, T., Huang, W. P., Stromhaug, P. E. & Klionsky, D. J. Mechanism of cargo selection in the cytoplasm to vacuole targeting pathway. Dev. Cell 3, 825–837 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kamber, R. A., Shoemaker, C. J. & Denic, V. Receptor-bound targets of selective autophagy use a scaffold protein to activate the Atg1 kinase. Mol. Cell 59, 372–381 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yorimitsu, T. & Klionsky, D. J. Atg11 links cargo to the vesicle-forming machinery in the cytoplasm to vacuole targeting pathway. Mol. Biol. Cell 16, 1593–1605 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Turco, E. et al. FIP200 claw domain binding to p62 promotes autophagosome formation at ubiquitin condensates. Mol. Cell 74, 330–346.e11 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, J. et al. Toward an understanding of the protein interaction network of the human liver. Mol. Syst. Biol. 7, 536 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ravenhill, B. J. et al. The cargo receptor NDP52 initiates selective autophagy by recruiting the ULK complex to cytosol-invading bacteria. Mol. Cell 74, 320–329.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vargas, J. N. S. et al. Spatiotemporal control of ULK1 activation by NDP52 and TBK1 during selective autophagy. Mol. Cell 74, 347–362.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shi, X., Chang, C., Yokom, A. L., Jensen, L. E. & Hurley, J. H. The autophagy adaptor NDP52 and the FIP200 coiled-coil allosterically activate ULK1 complex membrane recruitment. eLife 9, e59099 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yamano, K. et al. Critical role of mitochondrial ubiquitination and the OPTN–ATG9A axis in mitophagy. J. Cell Biol. 219, e201912144 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Itakura, E., Kishi-Itakura, C., Koyama-Honda, I. & Mizushima, N. Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy. J. Cell Sci. 125, 1488–1499 (2012).

    CAS  PubMed  Google Scholar 

  33. Zaffagnini, G. & Martens, S. Mechanisms of selective autophagy. J. Mol. Biol. 428, 1714–1724 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Knorr, R. L., Dimova, R. & Lipowsky, R. Curvature of double-membrane organelles generated by changes in membrane size and composition. PLoS ONE 7, e32753 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bahrami, A. H., Lin, M. G., Ren, X., Hurley, J. H. & Hummer, G. Scaffolding the cup-shaped double membrane in autophagy. PLoS Comput. Biol. 13, e1005817 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Bjorkoy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zaffagnini, G. et al. p62 filaments capture and present ubiquitinated cargos for autophagy. EMBO J. 37, e98308 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sun, D., Wu, R., Zheng, J., Li, P. & Yu, L. Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. Cell Res. 28, 405–415 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ciuffa, R. et al. The selective autophagy receptor p62 forms a flexible filamentous helical scaffold. Cell Rep. 11, 748–758 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Kageyama, S. et al. p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response. Nat. Commun. 12, 16 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sánchez-Martín, P. et al. NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system. EMBO Rep. 21, e48902 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Agudo-Canalejo, J. et al. Wetting regulates autophagy of phase-separated compartments and the cytosol. Nature 591, 142–146 (2021).

    Article  CAS  PubMed  Google Scholar 

  43. Suzuki, K., Kubota, Y., Sekito, T. & Ohsumi, Y. Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12, 209–218 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Koyama-Honda, I., Itakura, E., Fujiwara, T. K. & Mizushima, N.Temporal analysis of recruitment of mammalian ATG proteins to the autophagosome formation site. Autophagy 9, 1491–1499 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Mei, Y. et al. Intrinsically disordered regions in autophagy proteins. Proteins 82, 565–578 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Jung, C. H. et al. ULK–Atg13–FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992–2003 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lin, M. G. & Hurley, J. H. Structure and function of the ULK1 complex in autophagy. Curr. Opin. Cell Biol. 39, 61–68 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shi, X. et al. ULK complex organization in autophagy by a C-shaped FIP200 N-terminal domain dimer. J. Cell Biol. 219, e201911047 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wallot-Hieke, N. et al. Systematic analysis of ATG13 domain requirements for autophagy induction. Autophagy 14, 743–763 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hieke, N. et al. Expression of a ULK1/2 binding-deficient ATG13 variant can partially restore autophagic activity in ATG13-deficient cells. Autophagy 11, 1471–1483 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fujioka, Y. et al. Structural basis of starvation-induced assembly of the autophagy initiation complex. Nat. Struct. Mol. Biol. 21, 513–521 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Yamamoto, H. et al. The intrinsically disordered protein Atg13 mediates supramolecular assembly of autophagy initiation complexes. Dev. Cell 38, 86–99 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Ragusa, M. J., Stanley, R. E. & Hurley, J. H. Architecture of the Atg17 complex as a scaffold for autophagosome biogenesis. Cell 151, 1501–1512 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fujioka, Y. et al. Phase separation organizes the site of autophagosome formation. Nature 578, 301–305 (2020).

    Article  CAS  PubMed  Google Scholar 

  55. Geng, J., Baba, M., Nair, U. & Klionsky, D. J. Quantitative analysis of autophagy-related protein stoichiometry by fluorescence microscopy. J. Cell Biol. 182, 129–140 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lin, M. G., Schoneberg, J., Davies, C. W., Ren, X. & Hurley, J. H. The dynamic Atg13-free conformation of the Atg1 EAT domain is required for phagophore expansion. Mol. Biol. Cell 15, 1228–1237 (2018).

    Article  Google Scholar 

  57. Lyon, A. S., Peeples, W. B. & Rosen, M. K. A framework for understanding the functions of biomolecular condensates across scales. Nat. Rev. Mol. Cell Biol. 22, 215–235 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Dooley, H. C. et al. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12–5–16L1. Mol. Cell 55, 238–252 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fracchiolla, D., Chang, C., Hurley, J. H. & Martens, S. A PI3K–WIPI2 positive feedback loop allosterically activates LC3 lipidation in autophagy. J. Cell Biol. 219, e201912098 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Chang, C. et al. Reconstitution of cargo-induced LC3 lipidation in mammalian selective autophagy. Preprint at bioRxiv https://doi.org/10.1101/2021.01.08.425958 (2021).

  61. Axe, E. L. et al. Autophagosome formation from compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Prinz, W. A. & Hurley, J. H. A firehose for phospholipids. J. Cell Biol. 219, e202003132 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Shintani, T., Suzuki, K., Kamada, Y., Noda, T. & Ohsumi, Y. Apg2p functions in autophagosome formation on the perivacuolar structure. J. Biol. Chem. 276, 30452–30460 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, C. W. et al. Apg2 is a novel protein required for the cytoplasm to vacuole targeting, autophagy, and pexophagy pathways. J. Biol. Chem. 276, 30442–30451 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Zheng, J. X. et al. Architecture of the ATG2B–WDR45 complex and an aromatic Y/HF motif crucial for complex formation. Autophagy 13, 1870–1883 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chowdhury, S. et al. Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A–WIPI4 complex. Proc. Natl Acad. Sci. USA 115, E9792–E9801 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kumar, N. et al. VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites. J. Cell Biol. 217, 3625–3639 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Von Bulow, S. & Hummer, G. Kinetics of Atg2-mediated lipid transfer from the ER can account for phagophore expansion. Preprint at bioRxiv https://doi.org/10.1101/2020.05.12.090977 (2020).

  69. Li, P., Lees, J. A., Lusk, C. P. & Reinisch, K. M. Cryo-EM reconstruction of a VPS13 fragment reveals a long groove to channel lipids between membranes. J. Cell Biol. 219, e202001161 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Noda, T. et al. Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways. J. Cell Biol. 148, 465–479 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Guardia, C. M. et al. Structure of human ATG9A, the only transmembrane protein of the core autophagy machinery. Cell Rep. 31, 107837 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Orii, M., Tsuji, T., Ogasawara, Y. & Fujimoto, T. Transmembrane phospholipid translocation mediated by Atg9 is involved in autophagosome formation. J. Cell Biol. 220, e202009194 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mari, M. et al. An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis. J. Cell Biol. 190, 1005–1022 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yamamoto, H. et al. Atg9 vesicles are an important membrane source during early steps of autophagosome formation. J. Cell Biol. 198, 219–233 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sawa-Makarska, J. et al. Reconstitution of autophagosome nucleation defines Atg9 vesicles as seeds for membrane formation. Science 369, eaaz7714 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kishi-Itakura, C., Koyama-Honda, I., Itakura, E. & Mizushima, N. Ultrastructural analysis of autophagosome organization using mammalian autophagy-deficient cells. J. Cell Sci. 127, 4089–4102 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Ohnstad, A. E. et al. Receptor-mediated clustering of FIP200 bypasses the role of LC3 lipidation in autophagy. EMBO J. 29, e104948 (2020).

    Google Scholar 

  78. Schutter, M., Giavalisco, P., Brodesser, S. & Graef, M. Local fatty acid channeling into phospholipid synthesis drives phagophore expansion during autophagy. Cell 180, 135–149.e14 (2020).

    Article  PubMed  Google Scholar 

  79. Nishimura, T. et al. Autophagosome formation is initiated at phosphatidylinositol synthase-enriched ER subdomains. EMBO J. 36, 1719–1735 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Andrejeva, G. et al. De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy. Autophagy 16, 1044–1060 (2020).

    Article  CAS  PubMed  Google Scholar 

  81. Hurley, J. H. The ESCRT complexes. Crit. Rev. Biochem. Mol. Biol. 45, 463–487 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Vietri, M., Radulovic, M. & Stenmark, H. The many functions of ESCRTs. Nat. Rev. Mol. Cell Biol. 21, 25–42 (2020).

    Article  CAS  PubMed  Google Scholar 

  83. Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806–808 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Parkinson, N. et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 67, 1074–1077 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Lee, J. A., Beigneux, A., Ahmad, S. T., Young, S. G. & Gao, F. B. ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr. Biol. 17, 1561–1567 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Filimonenko, M. et al. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J. Cell Biol. 179, 485–500 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Takahashi, Y. et al. An autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure. Nat. Commun. 9, 2855 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Zhen, Y. et al. ESCRT-mediated phagophore sealing during mitophagy. Autophagy 16, 826–841 (2020).

    Article  CAS  PubMed  Google Scholar 

  89. Zhou, F. et al. Rab5-dependent autophagosome closure by ESCRT. J. Cell Biol. 218, 1908–1927 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Takahashi, Y. et al. VPS37A directs ESCRT recruitment for phagophore closure. J. Cell Biol. 218, 3336–3354 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Flower, T. G. et al. A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission. Nat. Struct. Mol. Biol. 27, 570–580 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by HFSP (RGP0026/2017 to J.H.H.) and NIH R01 GM111730 (to J.H.H.).

Author information

Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA

    Chunmei Chang, Liv E. Jensen & James H. Hurley

  2. California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA

    Chunmei Chang, Liv E. Jensen & James H. Hurley

Authors
  1. Chunmei Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liv E. Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James H. Hurley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James H. Hurley.

Ethics declarations

Competing interests

J.H.H. is a co-founder of Casma Therapeutics.

Additional information

Peer review information Nature Cell Biology thanks the anonymous reviewers for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chang, C., Jensen, L.E. & Hurley, J.H. Autophagosome biogenesis comes out of the black box. Nat Cell Biol 23, 450–456 (2021). https://doi.org/10.1038/s41556-021-00669-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41556-021-00669-y

This article is cited by

Search

Advanced search

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