Noncanonical inhibition of caspase-3 by a nuclear microRNA confers endothelial protection by autophagy in atherosclerosis
- 3 June 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (546)
- https://doi.org/10.1126/scitranslmed.aaz2294
Abstract
MicroRNAs (miRNAs) are versatile regulators of gene expression with profound implications for human disease including atherosclerosis, but whether they can exert posttranslational functions to control cell adaptation and whether such noncanonical features harbor pathophysiological relevance is unknown. Here, we show that miR-126-5p sustains endothelial integrity in the context of high shear stress and autophagy. Bound to argonaute-2 (Ago2), miR-126-5p forms a complex with Mex3a, which occurs on the surface of autophagic vesicles and guides its transport into the nucleus. Mutational studies and biophysical measurements demonstrate that Mex3a binds to the central U- and G-rich regions of miR-126-5p with nanomolar affinity via its two K homology domains. In the nucleus, miR-126-5p dissociates from Ago2 and binds to caspase-3 in an aptamer-like fashion with its seed sequence, preventing dimerization of the caspase and inhibiting its activity to limit apoptosis. The antiapoptotic effect of miR-126-5p outside of the RNA-induced silencing complex is important for endothelial integrity under conditions of high shear stress promoting autophagy: ablation of Mex3a or ATG5 in vivo attenuates nuclear import of miR-126-5p, aggravates endothelial apoptosis, and exacerbates atherosclerosis. In human plaques, we found reduced nuclear miR-126-5p and active caspase-3 in areas of disturbed flow. The direct inhibition of caspase-3 by nuclear miR-126-5p reveals a noncanonical mechanism by which miRNAs can modulate protein function.Keywords
Funding Information
- European Research Council (ERC AdG °692511)
- European Research Council (CoG°683145)
- Deutsche Forschungsgemeinschaft (SFB1123-A1)
- Deutsche Forschungsgemeinschaft (SFB1123-A10)
- Deutsche Forschungsgemeinschaft (SFB1123-B4)
- Deutsche Forschungsgemeinschaft (SFB1123-A2)
- Deutsche Forschungsgemeinschaft (SFB1123-A5)
- Deutsche Forschungsgemeinschaft (GRK1721)
- Deutsche Forschungsgemeinschaft (TRR267-A2)
- Deutsche Forschungsgemeinschaft (STE-1053/5-1)
- Deutsche Forschungsgemeinschaft (TRR267-A2)
- Deutsche Forschungsgemeinschaft (SFB1123-Z1)
This publication has 79 references indexed in Scilit:
- The Structure of Human Argonaute-2 in Complex with miR-20aCell, 2012
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesisNature, 2010
- COUP-TFII is Regulated by High Glucose in Endothelial CellsHormone and Metabolic Research, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- miR-126 Regulates Angiogenic Signaling and Vascular IntegrityDevelopmental Cell, 2008
- The Endothelial-Specific MicroRNA miR-126 Governs Vascular Integrity and AngiogenesisDevelopmental Cell, 2008
- MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1Proceedings of the National Academy of Sciences of the United States of America, 2008
- Angiogenesis in life, disease and medicineNature, 2005
- NMRPipe: A multidimensional spectral processing system based on UNIX pipesJournal of Biomolecular NMR, 1995