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CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis.
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2020-01-13 , DOI: 10.1073/pnas.1917112117
Sarah Hanna-Addams 1 , Shuzhen Liu 1 , Hua Liu 1, 2 , She Chen 3 , Zhigao Wang 4
Affiliation  

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.

中文翻译:

CK1α,CK1δ和CK1ε是使人RIPK3的丝氨酸227磷酸化以激活坏死病的坏死性成分。

坏死性坏死病是一种受调节的坏死细胞死亡途径,由称为坏死体的超分子复合物介导,它包含受体相互作用蛋白激酶1、3(RIPK1,RIPK3)和混合谱系激酶结构域样蛋白(MLKL)。已经证明在下游MLKL结合和坏死病进展中需要人RIPK3在丝氨酸227上的磷酸化(S227)。RIPK3的串联免疫沉淀显示酪蛋白激酶1(CK1)家族蛋白在坏死病诱导后与坏死体结合,并且这种相互作用取决于RIPK3的激酶活性。另外,在坏死病期间,CK1蛋白与RIPK3点共同定位。重要的是,CK1蛋白在体外和体内直接在S227处磷酸化RIPK3。CK1蛋白的丢失消除了S227的磷酸化并阻断了坏死性肾病。此外,在CK1识别基序中发生突变的RIPK3突变体无法在S227处被磷酸化,不与MLKL结合或磷酸化,并且无法激活坏死病。这些结果强烈暗示CK1蛋白是负责RIPK3-S227磷酸化的坏死组分。
更新日期:2020-01-29
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