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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2015

Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy

T. Zhou
  • Fonction : Auteur
J. Li
  • Fonction : Auteur
P. Zhao
H. Liu
D. Jia
  • Fonction : Auteur
H. Jia
  • Fonction : Auteur
L. He
  • Fonction : Auteur
Y. Cang
  • Fonction : Auteur
S. Boast
  • Fonction : Auteur
Y. H. Chen
  • Fonction : Auteur
M. Scherrer-Crosbie
  • Fonction : Auteur
S. P. Goff
  • Fonction : Auteur
B. Li
  • Fonction : Auteur

Résumé

Protein palmitoylation regulates many aspects of cell function and is carried out by acyl transferases that contain zf-DHHC motifs. The in vivo physiological function of protein palmitoylation is largely unknown. Here we generated mice deficient in the acyl transferase Aph2 (Ablphilin 2 or zf-DHHC16) and demonstrated an essential role for Aph2 in embryonic/postnatal survival, eye development, and heart development. Aph2(-/-) embryos and pups showed cardiomyopathy and cardiac defects including bradycardia. We identified phospholamban, a protein often associated with human cardiomyopathy, as an interacting partner and a substrate of Aph2. Aph2-mediated palmitoylation of phospholamban on cysteine 36 differentially alters its interaction with PKA and protein phosphatase 1 alpha, augmenting serine 16 phosphorylation, and regulates phospholamban pentamer formation. Aph2 deficiency results in phospholamban hypophosphorylation, a hyperinhibitory form. Ablation of phospholamban in Aph2(-/-) mice histologically and functionally alleviated the heart defects. These findings establish Aph2 as a critical in vivo regulator of cardiac function and reveal roles for protein palmitoylation in the development of other organs including eyes.

Dates et versions

hal-01850608 , version 1 (27-07-2018)

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Citer

T. Zhou, J. Li, P. Zhao, H. Liu, D. Jia, et al.. Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112 (51), pp.15666-71. ⟨10.1073/pnas.1518368112⟩. ⟨hal-01850608⟩
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