Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy

Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):15666-71. doi: 10.1073/pnas.1518368112. Epub 2015 Dec 7.

Abstract

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 α, 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.

Keywords: Aph2 gene; cardiac development; eye development; palmitoyl transferase; phospholamban.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / physiology*
  • Animals
  • COS Cells
  • Calcium-Binding Proteins / metabolism
  • Cardiomyopathies / etiology*
  • Carrier Proteins / physiology*
  • Chlorocebus aethiops
  • Echocardiography
  • Eye / embryology
  • Lipoylation
  • Mice
  • Phosphorylation

Substances

  • Calcium-Binding Proteins
  • Carrier Proteins
  • phospholamban
  • Acyltransferases
  • Zdhhc16 protein, mouse