TY  - JOUR
A1  - Rödig, Jens
A1  - Kowald, Lisa
A1  - Juretschke, Thomas
A1  - Karlowitz, Rebekka
A1  - Abhari, Behnaz
A1  - Rödig, Heiko
A1  - Fulda, Simone
A1  - Beli, Petra
A1  - Wijk, Sjoerd van
T1  - USP22 controls necroptosis by regulating receptor-interacting protein kinase 3 ubiquitination
T2  - EMBO reports
N2  - Dynamic control of ubiquitination by deubiquitinating enzymes is essential for almost all biological processes. Ubiquitin-specific peptidase 22 (USP22) is part of the SAGA complex and catalyzes the removal of mono-ubiquitination from histones H2A and H2B, thereby regulating gene transcription. However, novel roles for USP22 have emerged recently, such as tumor development and cell death. Apart from apoptosis, the relevance of USP22 in other programmed cell death pathways still remains unclear. Here, we describe a novel role for USP22 in controlling necroptotic cell death in human tumor cell lines. Loss of USP22 expression significantly delays TNFα/Smac mimetic/zVAD.fmk (TBZ)-induced necroptosis, without affecting TNFα-mediated NF-κB activation or extrinsic apoptosis. Ubiquitin remnant profiling identified receptor-interacting protein kinase 3 (RIPK3) lysines 42, 351, and 518 as novel, USP22-regulated ubiquitination sites during necroptosis. Importantly, mutation of RIPK3 K518 reduced necroptosis-associated RIPK3 ubiquitination and amplified necrosome formation and necroptotic cell death. In conclusion, we identify a novel role of USP22 in necroptosis and further elucidate the relevance of RIPK3 ubiquitination as crucial regulator of necroptotic cell death.
KW  - cancer specific survival
KW  - mixed lineage kinase domain-like
KW  - post-translational modifications
KW  - RIPK1
KW  - ubiquitin hydrolase
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63865
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-638657
SN  - 1469-3178
N1  - This work has been partially funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 259130777 – SFB 1177 (to P. B., S. F. and S. J. L. v. W.), FU 436/20-1 (to S.F. and S. J. L. v. W.) and WI 5171_1-1 (to S. J. L. v. W.), the Dr. Eberhard and Hilde Rüdiger Foundation (to S. J. L. v. W), the BMBF (to S. F.), the Deutsche Krebshilfe (70113680) (to S.F. and S. J. L. v. W.) and the Frankfurter Stiftung für krebskranke Kinder. The research in the lab of P. B. is supported by the German Research Foundation (Emmy Noether Program, BE 5342/1-1). The authors acknowledge C. Hugenberg for critical reading of the manuscript. Open access funding enabled and organized by Projekt DEAL.
VL  - 22
IS  - 2, art. e50163
SP  - 1
EP  - 21
PB  - EMBO Press; Wiley
CY  - Heidelberg; Hoboken, NJ [u.a.]
ER  -