Internalization of complement membrane attack complexes (MACs) assembles NLRP3 inflammasomes in endothelial cells (EC) and promotes IL-β-mediated tissue inflammation. Informed by proteomics analyses of FACS-sorted inflammasomes, we identify a protein complex modulating inflammasome activity on endosomes. ZFVYE21, a Rab5 effector, partners with Rubicon and RNF34, forming a “ZRR” complex that is stabilized in a Rab5- and ZFYVE21-dependent manner on early endosomes. There, Rubicon competitively disrupts inhibitory associations between caspase-1 and its pseudosubstrate, Flightless I (FliI), while RNF34 ubiquitinylates and degradatively removes FliI from the signaling endosome. The concerted actions of the ZRR complex increase pools of endosome-associated caspase-1 available for activation. The ZRR complex is assembled in human tissues, its associated signaling responses occur in three mouse models in vivo, and the ZRR complex promotes inflammation in a skin model of chronic rejection. The ZRR signaling complex reflects a potential therapeutic target for attenuating inflammasome-mediated tissue injury.

补体膜攻击复合物 （MAC） 的内化在内皮细胞 （EC） 中组装 NLRP3 炎性小体并促进 IL β介导的组织炎症。通过对 FACS 分选的炎性小体的蛋白质组学分析，我们确定了一种调节内体炎症小体活性的蛋白质复合物。ZFVYE21 是 Rab5 效应子，与 Rubicon 和 RNF34 合作，形成“ZRR”复合物，该复合物在早期内体上以 Rab5 和 ZFYVE21 依赖性方式稳定。在那里，Rubicon 竞争性地破坏 caspase-1 与其伪底物 Flightless I （FliI） 之间的抑制性结合，而 RNF34 泛素化并降解地从信号转导内体中去除 FliI。ZRR 复合物的协同作用增加了可用于激活的内体相关 caspase-1 的池。ZRR 复合物组装在人体组织中，其相关的信号反应发生在体内的三种小鼠模型中，ZRR 复合物在慢性排斥的皮肤模型中促进炎症。ZRR 信号转导复合物反映了减轻炎性小体介导的组织损伤的潜在治疗靶点。