Autophagy unleashes noncanonical microRNA functions.

First Authors Donato Santovito
Authors Donato Santovito, Virginia Egea, Kiril Bidzhekov, Lucia Natarelli, André Mourão, Xavier Blanchet, Kanin Wichapong, Maria Aslani, Coy Brunßen, Michael Horckmans, Michael Hristov, Arie Geerlof, Esther Lutgens, Mat J A P Daemen, Tilman M Hackeng, Christian Ries, Trian Chavakis, Henning Morawietz, Ronald Naumann, Philipp von Hundelshausen, Sabine Steffens, Johan Duchêne, Remco T A Megens, Michael Sattler, Christian Weber
Corresponding Authors
Last Authors Christian Weber
Journal Name Autophagy (Autophagy)
Volume
Issue
Article Number doi: 10.1080/15548627.2020.1830523
PubMed ID 33054575
WebOfScience Link WOS:000577630400001
Open Access false
Print Publication Date 2020-10-15
Online Publication Date
Abstract MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression which act by guiding AGO (argonaute) proteins to target RNA transcripts in the RNA-induced silencing complex (RISC). This macromolecular complex includes multiple additional components (e.g., TNRC6A) that allow for interaction with enzymes mediating inhibition of translation or RNA decay. However, miRNAs also reside in low-molecular weight complexes without being engaged in target repression, and their function in this context is largely unknown. Our recent findings show that endothelial cells exposed to protective high-shear stress or MTORC inhibition activate the macroautophagy/autophagy machinery to sustain viability by promoting differential trafficking of MIR126 strands and by enabling unconventional features of MIR126-5p. Whereas MIR126-3p is degraded upon autophagy activation, MIR126-5p interacts with the RNA-binding protein MEX3A to form a ternary complex with AGO2. This complex forms on the autophagosomal surface and facilitates its nuclear localization. Once in the nucleus, MIR126-5p dissociates from AGO2 and establishes aptamer-like interactions with the effector CASP3 (caspase 3). The binding to MIR126-5p prevents dimerization and proper active site formation of CASP3, 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 the progression of atherosclerosis. The direct inhibition of CASP3 by MIR126-5p reveals a non-canonical mechanism by which miRNAs can modulate protein function and mediate the autophagy-apoptosis crosstalk.
Cover Image
Affiliated With Transgenic Core Facility
Selected By Transgenic Core Facility
Acknowledged Services
Publication Status Published
Edoc Link
Sfx Link
DOI 10.1080/15548627.2020.1830523
Display Publisher Download Only false
Visible On MPI-CBG Website true
PDF Downloadable true
Created By naumann
Added Date 2020-10-21
Last Edited By herbst
Last Edited Date 2020-10-28 09:57:41.578
Library ID 7816
Document ID
Entry Complete true
eDoc Compliant true
Include in Edoc Report true
In Pure
Ready for eDoc Export
Author Affiliations Complete false