XIAP controls RIPK2 signaling by preventing its deposition in speck-like structures
XIAP controls RIPK2 signaling by preventing its deposition in speck-like structures
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DOI：
10.26508/lsa.201900346
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发表时间：
2019-08-01
影响因子：
4.4
通讯作者：
Kufer, Thomas A.
中科院分区：
文献类型：
--
作者：
Ellwanger, Kornelia;Briese, Selina;Kufer, Thomas A.
受体相互作用丝氨酸/苏氨酸激酶2（RIPK 2）对于将模式识别受体NOD 1和NOD 2的激活与细胞信号传导事件联系起来是必不可少的。最近，研究表明RIPK 2在体外可以形成更高级的分子结构。在这里，我们证明，RIPK 2形式洗涤剂不溶性复合物在宿主细胞的胞质溶胶感染后，侵入性肠道致病菌。这些结构的形成发生在NF-κ B活化后，并依赖于caspase活化和NOD 1或NOD 2的募集结构域。激活后的复合物形成需要RIPK 2在Y 474处的自磷酸化，并受到S176处磷酸化的影响。我们发现E3连接酶X连锁凋亡抑制因子（XIAP）可以抵消RIPK 2的复合物形成，因此RIPK 2中XIAP泛素化位点的突变可以增强复合物的形成。总之，我们的工作揭示了XIAP在RIPK 2调节中的新作用，并扩展了我们对RIPK 2翻译后修饰在NOD 1/2信号转导中的功能的认识。
The receptor interacting serine/threonine kinase 2 (RIPK2) is essential for linking activation of the pattern recognition receptors NOD1 and NOD2 to cellular signaling events. Recently, it was shown that RIPK2 can form higher order molecular structures in vitro. Here, we demonstrate that RIPK2 forms detergent insoluble complexes in the cytosol of host cells upon infection with invasive enteropathogenic bacteria. Formation of these structures occurred after NF-kappa B activation and depended on the caspase activation and recruitment domain of NOD1 or NOD2. Complex formation upon activation required RIPK2 autophosphorylation at Y474 and was influenced by phosphorylation at S176. We found that the E3 ligase X-linked inhibitor of apoptosis (XIAP) counteracts complex formation of RIPK2, accordingly mutation of the XIAP ubiquitylation sites in RIPK2 enhanced complex formation. Taken together, our work reveals novel roles of XIAP in the regulation of RIPK2 and expands our knowledge on the function of RIPK2 posttranslational modifications in NOD1/2 signaling.