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Santovito, D.* ; Egea, V.* ; Bidzhekov, K.* ; Natarelli, L.* ; Mourao, A. ; Blanchet, X.* ; Wichapong, K.* ; Aslani, M.* ; Brunßen, C.* ; Horckmans, M.* ; Hristov, M.* ; Geerlof, A. ; Lutgens, E.* ; Daemen, M.J.A.P.* ; Hackeng, T.* ; Ries, C.* ; Chavakis, T.* ; Morawietz, H.* ; Naumann, R.* ; Hundelshausen, P.V.* ; Steffens, S.* ; Duchêne, J.* ; Megens, R.T.A.* ; Sattler, M. ; Weber, C.*

Autophagy unleashes noncanonical microRNA functions.

Autophagy 16, 2294-2296 (2020)
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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 ofMIR126strands and by enabling unconventional features ofMIR126-5p. WhereasMIR126-3pis degraded upon autophagy activation,MIR126-5pinteracts 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,MIR126-5pdissociates from AGO2 and establishes aptamer-like interactions with the effector CASP3 (caspase 3). The binding toMIR126-5pprevents dimerization and proper active site formation of CASP3, thus inhibiting proteolytic activity and limiting apoptosis. Disrupting this pathwayin vivoby genetic deletion ofMex3aor by specific deficiency of endothelial autophagy aggravates endothelial apoptosis and exacerbates the progression of atherosclerosis. The direct inhibition of CASP3 byMIR126-5preveals a non-canonical mechanism by which miRNAs can modulate protein function and mediate the autophagy-apoptosis crosstalk.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Microrna ; Atherosclerosis ; Autophagy ; Mex3a ; Mir-126-5p ; Noncanonical Mirna Functions ; Endothelial Cells
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 1554-8627
e-ISSN 1554-8635
Journal Autophagy
Quellenangaben Volume: 16, Issue: 12, Pages: 2294-2296 Article Number: , Supplement: ,
Publisher Landes Bioscience
Publishing Place 530 Walnut Street, Ste 850, Philadelphia, Pa 19106 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
Grants European Research Council: [ERC]
Deutsche Forschungsgemeinschaft (DFG)
DOI 10.1080/15548627.2020.1830523
WOS ID WOS:000577630400001
Scopus ID 85092709841
PubMed ID 33054575
Erfassungsdatum 2020-11-05
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