title: Is SIRT2 required for necroptosis?
abstract: 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.
authors.affiliation: Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Newton
authors.affiliation: 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.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Hildebrand
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Rodriguez
authors.affiliation: 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.
authors.forename: Silvia
authors.initials: S
authors.lastname: Alvarez-Diaz
authors.affiliation: Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Petersen
authors.affiliation: Department of Biochemistry, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Saumil
authors.initials: S
authors.lastname: Shah
authors.affiliation: Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Dugger
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Chunzi
authors.initials: C
authors.lastname: Huang
authors.affiliation: Laboratory of Integrative and Systems Physiology, EPFL, CH-1015 Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
authors.affiliation: Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Department of Biochemistry, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Silke
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D009336:Necrosis / Q000201:enzymology*; D056565:Sirtuin 2 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D056565:Sirtuin 2