Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli

Abstract

Extracellular vesicle (EV)–cargo miRNAs mediate intercellular communications. How cells selectively sort the miRNAs into EVs remains unclear. Lee et al. demonstrate a novel mechanism by which functional miRNAs are selectively sorted into EVs via caveolin-1/hnRNPA2B1 complex. This process is regulated by stimulation-associated posttranslational modifications of both cav-1 and hnRNPA2B1.

Abstract

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.