Emerging evidence suggests that extracellular vesicle (EV)-containing miRNAs mediate intercellular communications in response to noxious stimuli. It remains unclear how a cell selectively sorts the cellular miRNAs into EVs. We report that caveolin-1 (cav-1) is essential for sorting of selected miRNAs into microvesicles (MVs), a main type of EVs generated by outward budding of the plasma membrane. We found that cav-1 tyrosine 14 (Y14)-phosphorylation leads to interactions between cav-1 and hnRNPA2B1, an RNA-binding protein. The cav-1/hnRNPA2B1 complex subsequently traffics together into MVs. Oxidative stress induces O-GlcNAcylation of hnRNPA2B1, resulting in a robustly altered hnRNPA2B1-bound miRNA repertoire. Notably, cav-1 pY14 also promotes hnRNPA2B1 O-GlcNAcylation. Functionally, macrophages serve as the principal recipient of epithelial MVs in the lung. MV-containing cav-1/hnRNPA2B1 complex-bound miR-17/93 activate tissue macrophages. Collectively, cav-1 is the first identified membranous protein that directly guides RNA-binding protein into EVs. Our work delineates a novel mechanism by which oxidative stress compels epithelial cells to package and secrete specific miRNAs and elicits an innate immune response.

中文翻译：

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Caveolin-1在有害刺激后选择性调节microRNA分类进入微泡。

新兴证据表明，含有细胞外囊泡（EV）的miRNA介导对有害刺激的细胞间通讯。尚不清楚细胞如何选择性地将细胞miRNA分类到EV中。我们报道，caveolin-1（cav-1）对于将选定的miRNA排序成微泡（MVs）是必不可少的，微泡是由质膜向外发芽产生的EV的主要类型。我们发现cav-1酪氨酸14（Y14）磷酸化导致cav-1和hnRNPA2B1，一种RNA结合蛋白之间的相互作用。随后，cav-1 / hnRNPA2B1复合体一起投放到MV中。氧化应激诱导hnRNPA2B1的O-GlcNAcy化，从而导致hnRNPA2B1结合的miRNA库发生强烈变化。值得注意的是，cav-1 pY14也促进hnRNPA2B1 O-GlcNAcylation。在功能上 巨噬细胞是肺中上皮MV的主要接受者。含MV的cav-1 / hnRNPA2B1复合物结合的miR-17 / 93激活组织巨噬细胞。总的来说，cav-1是第一个直接将RNA结合蛋白引导至EV的膜蛋白。我们的工作描述了一种新的机制，通过该机制氧化应激迫使上皮细胞包装和分泌特定的miRNA，并引发先天性免疫反应。