Autophagy unleashes noncanonical microRNA functions

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Donato Santovito - , Ludwig Maximilian University of Munich, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), National Research Council of Italy (Author)
  • Virginia Egea - , Ludwig Maximilian University of Munich (Author)
  • Kiril Bidzhekov - , Ludwig Maximilian University of Munich (Author)
  • Lucia Natarelli - , Ludwig Maximilian University of Munich, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • André Mourão - , Helmholtz Centre for Environmental Research (Author)
  • Xavier Blanchet - , Ludwig Maximilian University of Munich (Author)
  • Kanin Wichapong - , Maastricht University (Author)
  • Maria Aslani - , Ludwig Maximilian University of Munich, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Coy Brunßen - , Department of internal Medicine 3 (Author)
  • Michael Horckmans - , Université libre de Bruxelles (ULB) (Author)
  • Michael Hristov - , Ludwig Maximilian University of Munich (Author)
  • Arie Geerlof - , Helmholtz Centre for Environmental Research (Author)
  • Esther Lutgens - , Ludwig Maximilian University of Munich, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), University of Amsterdam (Author)
  • Mat J.A.P. Daemen - , University of Amsterdam (Author)
  • Tilman Hackeng - , Maastricht University (Author)
  • Christian Ries - , Ludwig Maximilian University of Munich (Author)
  • Triantafyllos Chavakis - , Institute of Clinical Chemistry and Laboratory Medicine (Author)
  • Henning Morawietz - , Department of internal Medicine 3 (Author)
  • Ronald Naumann - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Philipp Von Hundelshausen - , Ludwig Maximilian University of Munich, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Sabine Steffens - , Ludwig Maximilian University of Munich, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Johan Duchêne - , Ludwig Maximilian University of Munich (Author)
  • Remco T.A. Megens - , Ludwig Maximilian University of Munich, Maastricht University (Author)
  • Michael Sattler - , Helmholtz Centre for Environmental Research, Technical University of Munich (Author)
  • Christian Weber - , Ludwig Maximilian University of Munich, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), Maastricht University (Author)

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.

Details

Original languageEnglish
Pages (from-to)2294-2296
Number of pages3
JournalAutophagy
Volume16
Issue number12
Publication statusPublished - 2020
Peer-reviewedYes

External IDs

PubMed 33054575

Keywords

ASJC Scopus subject areas

Keywords

  • Atherosclerosis, Autophagy, Endothelial cells, MEX3A, microRNA, miR-126-5p, Noncanonical miRNA functions