CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis

Sarah Hanna-Addams, Shuzhen Liu, Hua Liu, She Chen, Zhigao Wang

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Necroptosis is a regulated necrotic cell death pathway, mediated by a supermolecular complex called the necrosome, which contains receptor-interacting protein kinase 1 and 3 (RIPK1, RIPK3) and mixed-lineage kinase domain-like protein (MLKL). Phosphorylation of human RIPK3 at serine 227 (S227) has been shown to be required for downstream MLKL binding and necroptosis progression. Tandem immunoprecipitation of RIPK3 reveals that casein kinase 1 (CK1) family proteins associate with the necrosome upon necroptosis induction, and this interaction depends on the kinase activity of RIPK3. In addition, CK1 proteins colocalize with RIPK3 puncta during necroptosis. Importantly, CK1 proteins directly phosphorylate RIPK3 at S227 in vitro and in vivo. Loss of CK1 proteins abolishes S227 phosphorylation and blocks necroptosis. Furthermore, a RIPK3 mutant with mutations in the CK1 recognition motif fails to be phosphorylated at S227, does not bind or phosphorylate MLKL, and is unable to activate necroptosis. These results strongly suggest that CK1 proteins are necrosome components which are responsible for RIPK3-S227 phosphorylation.

Original languageEnglish (US)
Pages (from-to)1962-1970
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number4
DOIs
StatePublished - Jan 28 2020

Keywords

  • MLKL
  • RIPK3 phosphorylation
  • casein kinase 1
  • necroptosis
  • necrosome

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis'. Together they form a unique fingerprint.

  • Cite this