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

Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy.

Author information

1
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China; Institute of Molecular and Cell Biology, Proteos, Singapore 138673;
2
XinHua Hospital, Shanghai Jiao Tong University, Shanghai 200092, China;
3
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China;
4
Institute of Molecular and Cell Biology, Proteos, Singapore 138673;
5
Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University College for Physicians and Surgeons, New York, NY 10032; Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China;
6
Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University College for Physicians and Surgeons, New York, NY 10032; Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, United Kingdom;
7
East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
8
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114.
9
Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University College for Physicians and Surgeons, New York, NY 10032; spg1@cumc.columbia.edu libj@sjtu.edu.cn.
10
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China; East Hospital, Tongji University School of Medicine, Shanghai 200120, China; spg1@cumc.columbia.edu libj@sjtu.edu.cn.

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

PMID:
26644582
PMCID:
PMC4697436
DOI:
10.1073/pnas.1518368112
[Indexed for MEDLINE]
Free PMC Article

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