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Edited by Xiaodong Wang, National Institute of Biological Sciences, Beijing, China, and approved December 20, 2019 (received for review October 1, 2019)
Significance
Necroptosis is a form of cell death implicated in many human diseases. A series of requirements has to be fulfilled before the cell makes the ultimate decision to die. One such essential event in necroptosis is the phosphorylation of RIPK3. It has previously been suggested that RIPK3 might phosphorylate itself. Here we discover that CK1 family kinases directly phosphorylate RIPK3. In cells without CK1 proteins, RIPK3 is not phosphorylated and the cells remain alive when exposed to necroptosis-inducing signals. Additionally, when cells express a form of RIPK3 which cannot be recognized by CK1, the cells also remain alive. This work defines a step in the necroptosis pathway and identifies potential targets for intervening necroptosis-associated diseases.
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: zhigao.wang{at}utsouthwestern.edu.
Author contributions: S.H.-A. and Z.W. designed research; S.H.-A., S.L., H.L., S.C., and Z.W. performed research; S.H.-A. and Z.W. analyzed data; and S.H.-A. and Z.W. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
Published under the PNAS license.
CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis
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