Author | Le Dour, Caroline | |
Author | Chatzifrangkeskou, Maria | |
Author | Macquart, Coline | |
Author | Magiera, Maria M. | |
Author | Peccate, Cécile | |
Author | Jouve, Charlène | |
Author | Virtanen, Laura | |
Author | Heliö, Tina | |
Author | Aalto-Setälä, Katriina | |
Author | Crasto, Silvia | |
Author | Cadot, Bruno | |
Author | Cardoso, Déborah | |
Author | Mougenot, Nathalie | |
Author | Adesse, Daniel | |
Author | Di Pasquale, Elisa | |
Author | Hulot, Jean-Sébastien | |
Author | Taimen, Pekka | |
Author | Janke, Carsten | |
Author | Muchir, Antoine | |
Access date | 2022-12-29T11:56:52Z | |
Available date | 2022-12-29T11:56:52Z | |
Document date | 2022 | |
Citation | LE DOUR, Caroline et al. Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations. Nature Comunications, v. 13, 7886, p. 1 - 21, 2022. | en_US |
ISSN | 2041-1723 | en_US |
URI | https://www.arca.fiocruz.br/handle/icict/56221 | |
Language | eng | en_US |
Publisher | Nature | en_US |
Rights | open access | |
Subject in Portuguese | Interação actina-microtúbulos do citoesqueleto | en_US |
Subject in Portuguese | Mediada pela sinalização MRTF-A/SRF | en_US |
Subject in Portuguese | Promove cardiomiopatia dilatada | en_US |
Subject in Portuguese | Causada por mutações LMNA | en_US |
Title | Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations | en_US |
Type | Article | |
DOI | 10.1038/s41467-022-35639-x | |
Abstract | Mutations in the lamin A/C gene (LMNA) cause dilated cardiomyopathy associated
with increased activity of ERK1/2 in the heart. We recently showed that
ERK1/2 phosphorylates cofilin-1 on threonine 25 (phospho(T25)-cofilin-1) that
in turn disassembles the actin cytoskeleton. Here, we show that inmuscle cells
carrying a cardiomyopathy-causing LMNA mutation, phospho(T25)-cofilin-1
binds to myocardin-related transcription factor A (MRTF-A) in the cytoplasm,
thus preventing the stimulation of serumresponse factor (SRF) in the nucleus.
Inhibiting the MRTF-A/SRF axis leads to decreased α-tubulin acetylation by
reducing the expression of ATAT1 gene encoding α-tubulin acetyltransferase 1.
Hence, tubulin acetylation is decreased in cardiomyocytes derived from male
patients with LMNA mutations and in heart and isolated cardiomyocytes from
Lmnap.H222P/H222P male mice. In Atat1 knockout mice, deficient for acetylated α-
tubulin, we observe left ventricular dilation andmislocalization of Connexin 43
(Cx43) in heart. Increasing α-tubulin acetylation levels in Lmnap.H222P/H222P mice
with tubastatin A treatment restores the proper localization of Cx43 and
improves cardiac function. In summary, we show for the first time an actinmicrotubule
cytoskeletal interplay mediated by cofilin-1 and MRTF-A/SRF,
promoting the dilated cardiomyopathy caused by LMNA mutations. Our
findings suggest that modulating α-tubulin acetylation levels is a feasible
strategy for improving cardiac function. | en_US |
Affilliation | Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France. | en_US |
Affilliation | Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France. | en_US |
Affilliation | Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France. | en_US |
Affilliation | Institut Curie, Université PSL, CNRSUMR3348, 91401 Orsay, France / Université Paris-Saclay, CNRS UMR3348, 91401 Orsay, France. | en_US |
Affilliation | Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France. | en_US |
Affilliation | Université de Paris, Paris Cardiovascular Research Center PARCC, INSERM, 75015 Paris, France. | en_US |
Affilliation | Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, 20520 Turku, Finland. | en_US |
Affilliation | Heart and Lung Centre, Helsinki University Central Hospital, University of Helsinki, 00290 Helsinki, Finland. | en_US |
Affilliation | Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere University, 33520 Tampere, Finland. | en_US |
Affilliation | Institute of Genetic and Biomedical Research (IRGB), UOS of Milan, National Research Council of Italy, Milan, Italy / Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano (MI), Italy. | en_US |
Affilliation | Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France. | en_US |
Affilliation | Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France. | en_US |
Affilliation | Sorbonne Université, INSERM, UMS28 Phénotypage du petit animal, Paris 75013, France. | en_US |
Affilliation | Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia Estrutural, Rio de Janeiro, RJ, Brasil. | en_US |
Affilliation | Institute of Genetic and Biomedical Research (IRGB), UOS of Milan, National Research Council of Italy, Milan, Italy / Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano (MI), Italy. | en_US |
Affilliation | Université de Paris, Paris Cardiovascular Research Center PARCC, INSERM, 75015 Paris, France. | en_US |
Affilliation | Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, 20520 Turku, Finland / Department of Pathology, Turku University Hospital, 20520 Turku, Finland. | en_US |
Affilliation | Institut Curie, Université PSL, CNRSUMR3348, 91401 Orsay, France / Université Paris-Saclay, CNRS UMR3348, 91401 Orsay, France. | en_US |
Affilliation | Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France. | en_US |
Subject | Actin-microtubule cytoskeletal interplay | en_US |
Subject | Mediated by MRTF-A/SRF signaling | en_US |
Subject | Promotes dilated cardiomyopath | en_US |
Subject | Caused by LMNA mutations | en_US |