한빛사 논문
Heedoo Lee1, Chunhua Li2, YangZhang2, Duo Zhang1, Leo E. Otterbein3, and Yang Jin1,*
1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University Medical Campus, Boston, MA;
2 Department of Computational Medicine and Bioinformatics Department of Biological Chemistry, The University of Michigan, Ann Arbor, MI;
3 Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA.
*Correspondence to Yang Jin
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.
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