Noncanonical function of nuclear miR-126-5p sustains endothelial integrity and prevents atherosclerosis

Comment: MicroRNAs (miRNAs) are versatile regulators of gene expression with profound implications for atherosclerosis, but whether they can exert additional functions to control cell adaptation was unknown. Our study unveiled an unexpected noncanonical function of miR-126-5p that sustain endothelial integrity. Endothelial cells exposed to protective high-shear stress activate the autophagy machinery which facilitate the interaction of miR-126-5p with the RNA-binding protein Mex3a to form a ternary complex with AGO2. This complex forms on the surface of autophagic vesicles to drive its nuclear localization. Once in the nucleus, miR-126-5p dissociates from AGO2 and establishes aptamer-like interactions with the effector caspase-3. The binding to miR-126-5p prevents dimerization and proper active site formation of caspase-3, thus inhibiting proteolytic activity and limiting apoptosis. Disrupting this pathway in vivo by genetic deletion of Mex3a or by specific deficiency of endothelial autophagy aggravates endothelial apoptosis and exacerbates atherosclerosis. Taken together, our findings reveal an important pathway composed of sequential miRNA-protein interaction which preserve endothelial integrity. Although further studies will be required, we foresee a potential therapeutic relevance in modulating this pathway to prevent endothelial dysfunction in atherosclerosis and in conditions where viability of the endothelium is crucial for a cardiovascular outcome (e.g. reendothelialization following angioplasty).

Figure legend. Summary of the MEX3A-guided nuclear miR-126-5p pathway. (1) Atheroprotective high shear stress (HSS), activation of KLF2 (Kruppel like factor 2), and mTORC-inhibition by rapamycin favors the assembly of a ternary complex of miR-126-5p with Mex3a and AGO2. (2) This complex localizes on the extraluminal surface of autophagosome, which preserves it from degradation and leads to its nuclear transfer. (3) In the nucleus, miR-126-5p dissociates from AGO2 and Mex3a and becomes available for binding the effector caspase, caspase-3 (CASP3), which can be transferred to the nucleus when activated.