HSP90 activity is required for MLKL oligomerisation and membrane translocation and the induction of necroptotic cell death

Cell Death & Disease
A V JacobsenJames M Murphy

Abstract

Necroptosis is a caspase-independent form of regulated cell death that has been implicated in the development of a range of inflammatory, autoimmune and neurodegenerative diseases. The pseudokinase, Mixed Lineage Kinase Domain-Like (MLKL), is the most terminal known obligatory effector in the necroptosis pathway, and is activated following phosphorylation by Receptor Interacting Protein Kinase-3 (RIPK3). Activated MLKL translocates to membranes, leading to membrane destabilisation and subsequent cell death. However, the molecular interactions governing the processes downstream of RIPK3 activation remain poorly defined. Using a phenotypic screen, we identified seven heat-shock protein 90 (HSP90) inhibitors that inhibited necroptosis in both wild-type fibroblasts and fibroblasts expressing an activated mutant of MLKL. We observed a modest reduction in MLKL protein levels in human and murine cells following HSP90 inhibition, which was only apparent after 15 h of treatment. The delayed reduction in MLKL protein abundance was unlikely to completely account for defective necroptosis, and, consistent with this, we also found inhibition of HSP90 blocked membrane translocation of activated MLKL. Together, these findings implicate HSP90 ...Continue Reading

References

Feb 28, 2002·Molecular Cell·Guoqing ChenDavid V Goeddel
Nov 21, 2002·The Journal of Biological Chemistry·Tom Vanden BerghePeter Vandenabeele
Aug 27, 2003·The Journal of Biological Chemistry·Cristen PantanoYvonne Janssen-Heininger
May 11, 2005·Biochemical and Biophysical Research Communications·Yumiko AoyagiTakashi Tsuruo
Mar 21, 2006·The Journal of Biological Chemistry·Claudia BossenPascal Schneider
Apr 28, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Rong LiOra Bernard
Jun 24, 2006·Bioscience, Biotechnology, and Biochemistry·Kazuya TerasawaYasufumi Minami
Sep 14, 2006·The Journal of Biological Chemistry·Colleen FearnsTsung-Hsien Chuang
Aug 31, 2007·The Journal of Biological Chemistry·Michael HinzClaus Scheidereit
Mar 10, 2009·The Journal of Biological Chemistry·Jungmook LyuWange Lu
Jan 20, 2010·Cell Stress & Chaperones·Candice S Gerbin, Ralf Landgraf
Apr 24, 2010·Cell Host & Microbe·Jason W UptonEdward S Mocarski
Aug 31, 2010·Genes & Development·Hiroyuki TakaiNikola P Pavletich
Aug 26, 2011·The Journal of Biological Chemistry·Tariq S AdwanMary E Reyland
Aug 30, 2011·Biochimica Et Biophysica Acta·Maria A Theodoraki, Avrom J Caplan
Sep 17, 2011·Nature·Claudia GüntherChristoph Becker
Nov 30, 2011·Proceedings of the National Academy of Sciences of the United States of America·Sudan HeXiaodong Wang
Mar 17, 2012·Proceedings of the National Academy of Sciences of the United States of America·Jie ZhaoZheng-Gang Liu
Feb 16, 2013·Genetics·Jennifer LachowiecChristine Queitsch
Apr 16, 2013·Cell Biochemistry and Function·Seung Yeon ParkYoung Sik Cho
Sep 10, 2013·Immunity·James M MurphyWarren S Alexander
Sep 11, 2013·The Journal of Biological Chemistry·William J KaiserEdward S Mocarski
Dec 11, 2013·The American Journal of Gastroenterology·Maria PierdomenicoSalvatore Cucchiara

❮ Previous
Next ❯

Citations

Feb 13, 2016·Cell Death and Differentiation·M C TanzerJ M Murphy
Jan 28, 2017·Trends in Pharmacological Sciences·Kelby W WegnerAlexei Degterev
Dec 22, 2016·Immunology and Cell Biology·Emma J PetrieJames M Murphy
Mar 2, 2018·Journal of Cellular and Molecular Medicine·Tao XuJianxun Wang
Dec 13, 2017·Cell Death and Differentiation·Marta B AfonsoCecília M P Rodrigues
Apr 15, 2017·Biochemical Society Transactions·James M MurphyPatrick A Eyers
Nov 3, 2017·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Akira Sato
Oct 21, 2018·Cell Death and Differentiation·Daniel Frank, James E Vince
Jan 25, 2018·Cell Death and Differentiation·Lorenzo GalluzziGuido Kroemer
Feb 3, 2019·Journal of Cell Science·Daniel FrankLisa M Lindqvist
Aug 17, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Paras K MishraTakashi Matsui
Nov 13, 2019·Cold Spring Harbor Perspectives in Biology·James M Murphy
Oct 19, 2016·Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban·Shuang ChenKun Xiong
Dec 14, 2016·Annual Review of Pathology·Lorenzo GalluzziGuido Kroemer
Nov 7, 2016·Pathogens and Disease·Alexandria M Palaferri Schieber, Janelle S Ayres
Aug 15, 2019·Science Signaling·António J M RibeiroPatrick A Eyers
Nov 14, 2019·Cell Death & Disease·Tamás MolnárGábor Koncz
Sep 19, 2020·Molecular & Cellular Oncology·Andrea N Johnston, Zhigao Wang
Apr 6, 2019·Cell Research·Daolin TangGuido Kroemer
Apr 3, 2020·Proceedings of the National Academy of Sciences of the United States of America·Emma J PetrieJames M Murphy
Sep 26, 2020·Frontiers in Cell and Developmental Biology·Benedikt KolbrinkStefan Krautwald
Feb 6, 2019·Proceedings of the National Academy of Sciences of the United States of America·Zheming WuJunying Yuan
Jun 18, 2017·Biochemical Society Transactions·Annette V Jacobsen, James M Murphy
Apr 29, 2020·International Journal of Molecular Sciences·Mariusz L Hartman
Mar 12, 2020·Proceedings of the National Academy of Sciences of the United States of America·Andrea N JohnstonZhigao Wang
Oct 31, 2020·The EMBO Journal·Hector Flores-RomeroAna J Garcia-Saez
Jan 20, 2021·Cell Death and Differentiation·Yanxiang MengJames M Murphy
Jul 4, 2020·Seminars in Cell & Developmental Biology·Zhijun Liu, Francis Ka-Ming Chan
Mar 1, 2021·European Journal of Pharmacology·Tetsuro MarunouchiKouichi Tanonaka
Jun 20, 2017·Current Opinion in Chemical Biology·Ying LiJunying Yuan
Apr 3, 2021·Cell Death & Disease·Joanne M HildebrandAbeer Fadda
Oct 17, 2020·Journal of Molecular Cell Biology·Lu LiXiawei Wei

❮ Previous
Next ❯

Methods Mentioned

BETA
thermal shift
flow cytometry
pulldown
transfection
size-exclusion chromatography

Related Concepts

Related Feeds

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.

Apoptotic Caspases

Apoptotic caspases belong to the protease enzyme family and are known to play an essential role in inflammation and programmed cell death. Here is the latest research.