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.

  • Brief Communications Arising
  • Published:

Is SIRT2 required for necroptosis?

Nature volume 506, pages E4–E6 (2014)Cite this article

Subjects

Abstract

Arising from N. Narayan et al. Nature 492, 199–204 (2012)10.1038/nature11700

Sirtuins can promote deacetylation of a wide range of substrates in diverse cellular compartments to regulate many cellular processes1,2; recently, Narayan et al.3 reported that SIRT2 was required for necroptosis on the basis of their findings that SIRT2 inhibition, knockdown or knockout prevented necroptosis. We sought to confirm and explore the role of SIRT2 in necroptosis and tested four different sources of the SIRT2 inhibitor AGK2, three independent short interfering RNAs (siRNAs) against Sirt2, and cells from two independently generated Sirt2−/− mouse strains; however, we were unable to show that inhibiting or depleting SIRT2 protected cells from necroptosis. Furthermore, Sirt2−/− mice succumbed to tumour-necrosis factor (TNF)-induced systemic inflammatory response syndrome (SIRS) more rapidly than wild-type mice, whereas Ripk3−/− mice were resistant. Our results therefore question the importance of SIRT2 in the necroptosis cell death pathway.

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

Figure 1: Neither chemical inhibition nor genetic depletion of SIRT2 inhibits TNF-induced necroptosis.
Figure 2: Appendix Figure 1 Neither chemical inhibition nor genetic depletion of SIRT2 inhibits TNF-induced necroptosis.

Similar content being viewed by others

References

  1. Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nature Rev. Mol. Cell Biol. 13, 225–238 (2012)

    Article  CAS  Google Scholar 

  2. Sebastian, C., Satterstrom, F. K., Haigis, M. C. & Mostoslavsky, R. From sirtuin biology to human diseases: an update. J. Biol. Chem. 287, 42444–42452 (2012)

    Article  CAS  Google Scholar 

  3. Narayan, N. et al. The NAD-dependent deacetylase SIRT2 is required for programmed necrosis. Nature 492, 199–204 (2012)

    Article  ADS  CAS  Google Scholar 

  4. Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1–RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009)

    Article  CAS  Google Scholar 

  5. He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009)

    Article  CAS  Google Scholar 

  6. Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009)

    Article  ADS  CAS  Google Scholar 

  7. Outeiro, T. F. et al. Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317, 516–519 (2007)

    Article  ADS  CAS  Google Scholar 

  8. Duprez, L. et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35, 908–918 (2011)

    Article  CAS  Google Scholar 

  9. Günther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011)

    Article  ADS  Google Scholar 

  10. Piao, X. et al. c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. Sci. Signal. 5, ra93 (2012)

    Article  Google Scholar 

  11. Welz, P. S. et al. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330–334 (2011)

    Article  ADS  CAS  Google Scholar 

  12. Beirowski, B. et al. Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling. Proc. Natl Acad. Sci. USA 108, E952–E961 (2011)

    Article  CAS  Google Scholar 

  13. Bobrowska, A., Donmez, G., Weiss, A., Guarente, L. & Bates, G. SIRT2 ablation has no effect on tubulin acetylation in brain, cholesterol biosynthesis or the progression of Huntington's disease phenotypes in vivo. PLoS ONE 7, e34805 (2012)

    Article  ADS  CAS  Google Scholar 

  14. Murphy, J. M. et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39, 443–453 (2013)

    Article  CAS  Google Scholar 

  15. Wang, L., Du, F. & Wang, X. TNF-α induces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008)

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Genentech, Inc., South San Francisco, 94080, California, USA

    Kim Newton, Sean Petersen, Debra L. Dugger, Avi Ashkenazi & Vishva M. Dixit

  2. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia,

    Joanne M. Hildebrand, Silvia Alvarez-Diaz, Andreas Strasser & John Silke

  3. Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia,

    Joanne M. Hildebrand, Silvia Alvarez-Diaz, Andreas Strasser & John Silke

  4. National Institute of Biological Sciences, Zhongguancun Life Science Park, Beijing, 102206, China

    Zhirong Shen

  5. Department of Immunology, St Jude Children’s Research Hospital, Memphis, 38105, Tennessee, USA

    Diego Rodriguez & Douglas R. Green

  6. Department of Biochemistry, Tufts University, Boston, 02111, Massachusetts, USA

    Saumil Shah & Alexei Degterev

  7. Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, 30322, Georgia, USA

    Chunzi Huang & William J. Kaiser

  8. Laboratory of Integrative and Systems Physiology, EPFL, CH-1015 Lausanne, Switzerland,

    Johan Auwerx

  9. Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB, 9052 Gent, Belgium,

    Peter Vandenabeele

  10. Department of Biomedical Molecular Biology, Ghent University, 9052 Gent, Belgium,

    Peter Vandenabeele

  11. Methusalem BOF09/01M00709, Ghent University, 9052 Gent, Belgium,

    Peter Vandenabeele

Authors
  1. Kim Newton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joanne M. Hildebrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhirong Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Diego Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Silvia Alvarez-Diaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sean Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Saumil Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Debra L. Dugger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chunzi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Johan Auwerx
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Peter Vandenabeele
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Douglas R. Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Avi Ashkenazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Vishva M. Dixit
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. William J. Kaiser
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Andreas Strasser
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Alexei Degterev
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. John Silke
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.N., J.M.H., Z.S., D.R., S.A.-D., S.P., S.S., D.L.D. and C.H. designed and performed experiments and analysed data; J.A., P.V., D.R.G., A.A., V.M.D., W.J.K., A.S., A.D. and J.S. planned the project and performed data analysis; K.N., J.M.H., J.A., P.V., D.R.G., A.A., V.M.D., W.J.K., A.S., A.D. and J.S. wrote paper.

Corresponding author

Correspondence to John Silke.

Ethics declarations

Competing interests

Competing Financial Interests Declared none.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Newton, K., Hildebrand, J., Shen, Z. et al. Is SIRT2 required for necroptosis?. Nature 506, E4–E6 (2014). https://doi.org/10.1038/nature13024

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature13024

This article is cited by

Comments

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.

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