Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy

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.palmitoyl transferase | phospholamban | cardiac development | eye development | Aph2 gene

Coding sequences of sarcoplasmic reticulum calcium ATPase regulatory peptides and expression of calcium regulatory genes in recurrent exertional rhabdomyolysis

“…Green highlight indicates highly conserved residues near the myoplasmic‐membrane interface of SERCA inhibitory peptides . Asterisk (*) indicates regulatory site residues . Question mark (?)…”

Identification and dynamics of the human ZDHHC16-ZDHHC6 palmitoylation cascade

“…Its name Ablphilin stems from its ability to interact with the non-receptor tyrosine kinase c-Abl at the ER surface ( Li et al, 2002 ). ZDHHC16/Aph2 is essential for embryonic and postnatal survival, eye and heart development in mice ( Zhou et al, 2015 ), for the proliferation of neural stem cells, where it is involved in the activation of the FGF/erk pathways ( Shi et al, 2016 ) and was reported to play a role in DNA damage response ( Cao et al, 2016 ). Our findings raise the possibility that some of these effects may involve ZDHHC6.…”

AKAP6 and phospholamban colocalize and interact in HEK‐293T cells and primary murine cardiomyocytes

“…Interestingly, Zhou et al. showed that palmitoylated PLN was identified at the perinuclear region of adult mouse cardiomyocytes, while perinuclear PLN was suggested to play a role in modulating Ca 2+ uptake and gene expression in adult mouse cardiomyocytes (Ljubojevic and Bers ; Wu et al. ; Chen et al.…”