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

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.

Interspecies Communication in Holobionts by Non-Coding RNA Exchange

“…The current accumulated knowledge about the mechanisms of ncRNAs sorting into secretory vesicles is focused on miRNAs in human and mammalian cells. Experimental evidence showed that the miRNA sorting into exosomes and other vesicles is mediated by RNA-binding and cytoskeleton proteins, following patterns that appear to be cell specific [40][41][42]. Interestingly, in human cells, the external perturbation of the expression of individual miRNAs or their cognate targets promotes bidirectional miRNA relocation from the cytoplasm to multivesicular bodies, controlling the miRNA sorting to exosomes [43].…”

Tumor-derived extracellular vesicles: molecular parcels that enable regulation of the immune response in cancer

“…Similarly, another RNA-binding protein, HNRNPA2B1, was reported to direct particular miRNA species to exosomes based on affinity for particular sequence motifs (Villarroya-Beltri et al, 2013). In addition, a recent study has found that a complex with caveolin-1 directs HNRNPA2B1 incorporation into microvesicles, and a post-translational modification induced by oxidative cell stress alters its selection for miRNA (Lee et al, 2019).…”

“…These models suggest that EVs indiscriminately incorporate miRNA; however, the majority of studies to date have actually found that EVs exhibit enrichment for particular RNA species, adding further complexity to the means of miRNA delivery (Li et al, 2013;Shurtleff et al, 2016;Wei et al, 2017). Different theories have been proposed to explain this phenomenon, such as a bias for particular sequence motifs or post-transcriptional RNA modifications that direct trafficking (Bolukbasi et al, 2012;Lee et al, 2019;Santangelo et al, 2016;Villarroya-Beltri et al, 2013). In addition, it appears that some miRNA species are principally trafficked to EVs by proteins other than those involved in classical miRNA maturation.…”

Ozone-induced changes in murine lung extracellular vesicle number and small RNA content

“…Alveolar macrophages and epithelial cells are two airway cell-types with readily apparent functional responses to O3 (1). Alveolar macrophages show reduced phagocytosis (17) and lung inflammation (33,43) are associated with altered airway EV miRNA profiles. In addition, there is growing evidence that EV miRNAs directly elicit airway cellular gene expression and phenotypic effects.…”