TY - JOUR
T1 - Nε-lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart
AU - Colussi, Claudia
AU - Rosati, Jessica
AU - Straino, Stefania
AU - Spallotta, Francesco
AU - Berni, Roberta
AU - Stilli, Donatella
AU - Rossi, Stefano
AU - Musso, Ezio
AU - Macchi, Emilio
AU - Mai, Antonello
AU - Sbardella, Gianluca
AU - Castellano, Sabrina
AU - Chimenti, Cristina
AU - Frustaci, Andrea
AU - Nebbioso, Angela
AU - Altucci, Lucia
AU - Capogrossi, Maurizio C.
AU - Gaetano, Carlo
PY - 2011/2/15
Y1 - 2011/2/15
N2 - Wanting to explore the epigenetic basis of Duchenne cardiomyopathy, we found that global histone acetylase activity was abnormally elevated and the acetylase P300/CBP-associated factor (PCAF) coimmunoprecipitated with connexin 43 (Cx43), which was Nε-lysine acetylated and lateralized in mdx heart. This observation was paralleled by Cx43 dissociation from N-cadherin and zonula occludens 1, whereas pp60-c-Src association was unaltered. In vivo treatment of mdx with the pan-histone acetylase inhibitor anacardic acid significantly reduced Cx43 Nε-lysine acetylation and restored its association to GAPjunctions (GJs) at intercalated discs. Noteworthy, in normal as well asmdxmice, the class IIa histone deacetylases 4 and 5 constitutively colocalized with Cx43 either at GJs or in the lateralized compartments. The class I histone deacetylase 3wasalso part of the complex. Treatment of normal controls with the histone deacetylase pan-inhibitor suberoylanilide hydroxamic acid (MC1568) or the class IIa-selective inhibitor 3-{4-[3-(3-fluorophenyl)-3-oxo-1-propen-1-yl]-1-methyl-1H-pyrrol-2-yl} -N-hydroxy-2-propenamide (MC1568) determined Cx43 hyperacetylation, dissociation from GJs, and distribution along the long axis of ventricular cardiomyocytes. Consistently, the histone acetylase activator pentadecylidenemalonate 1b (SPV106) hyperacetylated cardiac proteins, including Cx43, which assumed a lateralized position that partly reproduced the dystrophic phenotype. In the presence of suberoylanilide hydroxamic acid, cell to cell permeabilitywas significantly diminished, which is in agreement with a Cx43 close conformation in the consequence of hyperacetylation. Additional experiments, performed with Cx43 acetylation mutants, revealed, for the acetylated form of the molecule, a significant reduction in plasma membrane localization and a tendency to nuclear accumulation. These results suggest that Cx43 Nε-lysine acetylation may have physiopathological consequences for cell to cell coupling and cardiac function.
AB - Wanting to explore the epigenetic basis of Duchenne cardiomyopathy, we found that global histone acetylase activity was abnormally elevated and the acetylase P300/CBP-associated factor (PCAF) coimmunoprecipitated with connexin 43 (Cx43), which was Nε-lysine acetylated and lateralized in mdx heart. This observation was paralleled by Cx43 dissociation from N-cadherin and zonula occludens 1, whereas pp60-c-Src association was unaltered. In vivo treatment of mdx with the pan-histone acetylase inhibitor anacardic acid significantly reduced Cx43 Nε-lysine acetylation and restored its association to GAPjunctions (GJs) at intercalated discs. Noteworthy, in normal as well asmdxmice, the class IIa histone deacetylases 4 and 5 constitutively colocalized with Cx43 either at GJs or in the lateralized compartments. The class I histone deacetylase 3wasalso part of the complex. Treatment of normal controls with the histone deacetylase pan-inhibitor suberoylanilide hydroxamic acid (MC1568) or the class IIa-selective inhibitor 3-{4-[3-(3-fluorophenyl)-3-oxo-1-propen-1-yl]-1-methyl-1H-pyrrol-2-yl} -N-hydroxy-2-propenamide (MC1568) determined Cx43 hyperacetylation, dissociation from GJs, and distribution along the long axis of ventricular cardiomyocytes. Consistently, the histone acetylase activator pentadecylidenemalonate 1b (SPV106) hyperacetylated cardiac proteins, including Cx43, which assumed a lateralized position that partly reproduced the dystrophic phenotype. In the presence of suberoylanilide hydroxamic acid, cell to cell permeabilitywas significantly diminished, which is in agreement with a Cx43 close conformation in the consequence of hyperacetylation. Additional experiments, performed with Cx43 acetylation mutants, revealed, for the acetylated form of the molecule, a significant reduction in plasma membrane localization and a tendency to nuclear accumulation. These results suggest that Cx43 Nε-lysine acetylation may have physiopathological consequences for cell to cell coupling and cardiac function.
KW - Muscular dystrophy
KW - Protein acetylation
UR - http://www.scopus.com/inward/record.url?scp=79952613152&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79952613152&partnerID=8YFLogxK
U2 - 10.1073/pnas.1013124108
DO - 10.1073/pnas.1013124108
M3 - Article
C2 - 21282606
AN - SCOPUS:79952613152
VL - 108
SP - 2795
EP - 2800
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 7
ER -