PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation
PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation
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DOI：
10.1016/j.molcel.2018.05.016
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发表时间：
2018-06-07
期刊：
影响因子：
16
通讯作者：
Kim, You-Sun
中科院分区：
文献类型：
--
作者：
Choi, Seung-Won;Park, Han-Hee;Kim, You-Sun
受体相互作用蛋白激酶-3 （RIP3或RIPK3）是坏死性坏死的中心蛋白，但调控RIP3活性和稳定性的翻译后过程仍然知之甚少。在这里，我们发现pellino E3泛素蛋白连接酶1 （PELI1）是一种E3连接酶，靶向RIP3进行蛋白酶体依赖性降解。RIP3在T182上的磷酸化导致与PELI1的叉头相关（FHA）结构域相互作用，以及PELI1介导的k48连接的RIP3在K363上的多泛素化。同样的磷酸化事件对RIP3激酶活性也很重要；因此，PELI1优先针对激酶活性RIP3进行降解。peli1介导的RIP3降解可有效防止RIP3超激活引发的细胞死亡。重要的是，中毒性表皮坏死松解（TEN）患者角质形成细胞中RIP3表达上调与PELI1的低表达相关，提示PELI1的缺失可能在TEN的发病机制中发挥作用。我们提出PELI1可能控制RIP3的非故意激活，从而防止细胞异常死亡和维持细胞稳态。
Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is a central protein in necroptosis, but post-translational processes that regulate RIP3 activity and stability remain poorly understood. Here, we identify pellino E3 ubiquitin protein ligase 1 (PELI1) as an E3 ligase that targets RIP3 for proteasome-dependent degradation. Phosphorylation of RIP3 on T182 leads to interaction with the forkhead-associated (FHA) domain of PELI1 and PELI1-mediated K48-linked polyubiquitylation of RIP3 on K363. This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. PELI1-mediated RIP3 degradation effectively prevents cell death triggered by RIP3 hyperactivation. Importantly, upregulated RIP3 expression in keratinocytes from toxic epidermal necrolysis (TEN) patients is correlated with low expression of PELI1, suggesting that loss of PELI1 may play a role in the pathogenesis of TEN. We propose that PELI1 may function to control inadvertent activation of RIP3, thus preventing aberrant cell death and maintaining cellular homeostasis.