Distinct roles of RIP1-RIP3 hetero- and RIP3-RIP3 homo-interaction in mediating necroptosis
Distinct roles of RIP1-RIP3 hetero- and RIP3-RIP3 homo-interaction in mediating necroptosis
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RIP1-RIP3异源相互作用和RIP3-RIP3同源相互作用在介导坏死性凋亡中的不同作用
DOI：
10.1038/cdd.2014.77
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发表时间：
2014-11-01
影响因子：
12.4
通讯作者：
Han, J.
中科院分区：
文献类型：
--
作者：
Wu, X-N;Yang, Z-H;Han, J.
坏死性凋亡由称为坏死体的信号复合物介导，其中包含受体相互作用蛋白 (RIP)1、RIP3 和混合谱系激酶结构域样 (MLKL)。众所周知，RIP1 和 RIP3 通过其 RIP 同型相互作用基序 (RHIM) 结构域介导的寡聚化在坏死体中形成异二聚丝状支架，但基于该支架的信号传导事件尚未完全解决。通过使用诱导二聚体系统，我们发现 RIP1-RIP1 相互作用对于坏死性凋亡来说是可有可无的； RIP1-RIP3相互作用是坏死性凋亡信号传导所必需的，但如果没有额外的RIP3蛋白被招募到RIP1-RIP3异二聚体，则不会出现坏死性凋亡，并且与RIP1的相互作用促进RIP3招募其他RIP3； RIP3-RIP3相互作用是坏死性凋亡所必需的，并且RIP3-RIP3二聚化足以诱导坏死性凋亡； RIP3二聚体诱导的坏死性凋亡需要MLKL。我们进一步表明，RIP3 寡聚体在引发坏死性凋亡方面并不比 RIP3 二聚体更有效，这表明复合物中 RIP3 同源相互作用，而不是 RIP3 是否形成均聚物，对坏死性凋亡很重要。 RIP3 二聚化导致 RIP3 分子内自磷酸化，这是招募 MLKL 所必需的。有趣的是，二聚体中 RIP3 之一的磷酸化足以诱导坏死性凋亡。由于RIP1-RIP3异二聚体本身不能诱导坏死性凋亡，因此RIP1-RIP3异二聚体淀粉样原纤维不太可能直接传播坏死性凋亡。我们提出，RIP1-RIP3淀粉样蛋白复合物组装后的信号转导事件是淀粉样蛋白支架中的RIP3招募游离RIP3，随后RIP3自磷酸化，以及随后RIP3招募MLKL以执行坏死性凋亡。
Necroptosis is mediated by a signaling complex called necrosome, containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL). It is known that RIP1 and RIP3 form heterodimeric filamentous scaffold in necrosomes through their RIP homotypic interaction motif (RHIM) domain-mediated oligomerization, but the signaling events based on this scaffold has not been fully addressed. By using inducible dimer systems we found that RIP1-RIP1 interaction is dispensable for necroptosis; RIP1-RIP3 interaction is required for necroptosis signaling, but there is no necroptosis if no additional RIP3 protein is recruited to the RIP1-RIP3 heterodimer, and the interaction with RIP1 promotes the RIP3 to recruit other RIP3; RIP3-RIP3 interaction is required for necroptosis and RIP3-RIP3 dimerization is sufficient to induce necroptosis; and RIP3 dimer-induced necroptosis requires MLKL. We further show that RIP3 oligomer is not more potent than RIP3 dimer in triggering necroptosis, suggesting that RIP3 homo-interaction in the complex, rather than whether RIP3 has formed homo polymer, is important for necroptosis. RIP3 dimerization leads to RIP3 intramolecule autophosphorylation, which is required for the recruitment of MLKL. Interestingly, phosphorylation of one of RIP3 in the dimer is sufficient to induce necroptosis. As RIP1-RIP3 heterodimer itself cannot induce necroptosis, the RIP1-RIP3 heterodimeric amyloid fibril is unlikely to directly propagate necroptosis. We propose that the signaling events after the RIP1-RIP3 amyloid complex assembly are the recruitment of free RIP3 by the RIP3 in the amyloid scaffold followed by autophosphorylation of RIP3 and subsequent recruitment of MLKL by RIP3 to execute necroptosis.