Cells respond to inflammatory disease states by releasing exosomes containing highly specific protein and RNA cargos, but how inflammation alters cargo specificity and secretion of exosomes is unknown. We show that increases in exosome secretion induced by either viral infection or LPS/ATP exposure result from inflammasome activation and subsequent caspase-1–dependent cleavage of the trafficking adaptor protein RILP. This cleaved form of RILP promotes the movement of multivesicular bodies toward the cell periphery and induces selective exosomal miRNA cargo loading. We have identified a common short sequence motif present in miRNAs that are selectively loaded into exosomes after RILP cleavage. This motif binds the RNA binding protein FMR1 and directs miRNA loading into exosomes via interaction with components of the ESCRT (endosomal sorting complex required for transport) pathway. These results indicate that inflammasome-mediated RILP cleavage, and sequence-specific interactions between miRNAs and FMR1, play a significant role in exosome cargo loading and enhanced secretion during cellular inflammatory responses.

中文翻译：

---

RNA 结合蛋白 FMR1 控制炎症期间选择性外泌体 miRNA 负载

细胞通过释放含有高度特异性蛋白质和RNA货物的外泌体来应对炎症疾病状态，但炎症如何改变货物特异性和外泌体的分泌尚不清楚。我们发现，病毒感染或 LPS/ATP 暴露诱导的外泌体分泌增加是由于炎症小体激活和随后的运输接头蛋白 RILP 的 caspase-1 依赖性裂解所致。这种 RILP 的切割形式促进多囊泡体向细胞外周移动，并诱导选择性外泌体 miRNA 负载。我们已经鉴定了 miRNA 中存在的常见短序列基序，这些基序在 RILP 切割后选择性加载到外泌体中。该基序结合 RNA 结合蛋白 FMR1，并通过与 ESCRT（转运所需的内体分选复合物）途径的成分相互作用，引导 miRNA 加载到外泌体中。这些结果表明，炎症小体介导的 RILP 裂解以及 miRNA 和 FMR1 之间的序列特异性相互作用，在细胞炎症反应期间的外泌体货物装载和增强分泌中发挥着重要作用。