Is SIRT2 required for necroptosis?

Newton K; Hildebrand JM; Shen Z; Rodriguez D; Alvarez-Diaz S; Petersen S; Shah S; Dugger DL; Huang C; Auwerx J; Vandenabeele P; Green DR; Ashkenazi A; Dixit VM; Kaiser WJ; Strasser A; Degterev A; Silke J

doi:10.1038/nature13024

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Is SIRT2 required for necroptosis?

Newton K Genentech, Inc., South San Francisco, California 94080, USA.
Hildebrand JM 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
Shen Z National Institute of Biological Sciences, Zhongguancun Life Science Park, Beijing 102206, China.
Rodriguez D Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Alvarez-Diaz S 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
Petersen S Genentech, Inc., South San Francisco, California 94080, USA.
Shah S Department of Biochemistry, Tufts University, Boston, Massachusetts 02111, USA.
Dugger DL Genentech, Inc., South San Francisco, California 94080, USA.
Huang C Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Auwerx J Laboratory of Integrative and Systems Physiology, EPFL, CH-1015 Lausanne, Switzerland.
Vandenabeele P 1] Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB, 9052 Gent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, 9052 Gent, Belgium [3] Methusalem BOF09/01M00709, Ghent University, 9052 Gent, Belgium.
Green DR Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Ashkenazi A Genentech, Inc., South San Francisco, California 94080, USA.
Dixit VM Genentech, Inc., South San Francisco, California 94080, USA.
Kaiser WJ Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Strasser A 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
Degterev A Department of Biochemistry, Tufts University, Boston, Massachusetts 02111, USA.
Silke J 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.

2014-02-28

Published in:

Nature. - 2014

English Sirtuins can promote deacetylation of a wide range of substrates in diverse cellular compartments and regulate many cellular processes¹,². Recently Narayan et al., reported that SIRT2 was required for necroptosis based on their findings that SIRT2 inhibition, knock-down or knock-out 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 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 TNF induced Systemic Inflammatory Response Syndrome (SIRS) more rapidly than wild type mice while Ripk3−/− mice were resistant. Our results therefore question the importance of SIRT2 in the necroptosis cell death pathway.

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