USP22 controls necroptosis by regulating receptor-interacting protein kinase 3 ubiquitination

EMBO Rep. 2021 Feb 3;22(2):e50163. doi: 10.15252/embr.202050163. Epub 2020 Dec 28.

Abstract

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.

Keywords: RIPK1; cancer; mixed lineage kinase domain-like; post-translational modifications; ubiquitin hydrolase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Humans
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Necroptosis*
  • Necrosis
  • Receptor-Interacting Protein Serine-Threonine Kinases* / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction
  • Ubiquitin Thiolesterase*
  • Ubiquitination

Substances

  • NF-kappa B
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ubiquitin Thiolesterase
  • Usp22 protein, human