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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.* ; von Hundelshausen, P.* ; Steffens, S.* ; Duchêne, J.* ; Megens, R.T.A.* ; Sattler, M. ; Weber, C.*

Noncanonical inhibition of caspase-3 by a nuclear microRNA confers endothelial protection by autophagy in atherosclerosis.

Sci. Transl. Med. 12:eaaz2294 (2020)
Verlagsversion DOI PMC
Closed
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mex-3 Proteins; Web Server; In-vivo; Argonaute; Expression; Disease; Flow; Integration; Mechanisms; Complexes
Sprache englisch
Veröffentlichungsjahr 2020
HGF-Berichtsjahr 2020
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Zeitschrift Science Translational Medicine
Quellenangaben Band: 12, Heft: 546, Seiten: , Artikelnummer: eaaz2294 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503000-001
DOI 10.1126/scitranslmed.aaz2294
WOS ID WOS:000539151300005
Scopus ID 85086007896
PubMed ID 32493793
Erfassungsdatum 2020-06-10
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