title: 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.
authors.affiliation: 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;
authors.forename: Tielin
authors.initials: T
authors.lastname: Zhou
authors.affiliation: XinHua Hospital, Shanghai Jiao Tong University, Shanghai 200092, China;
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: XinHua Hospital, Shanghai Jiao Tong University, Shanghai 200092, China;
authors.forename: Peiquan
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Huijuan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, Singapore 138673;
authors.forename: Deyong
authors.initials: D
authors.lastname: Jia
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Hao
authors.initials: H
authors.lastname: Jia
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: 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;
authors.forename: Yong
authors.initials: Y
authors.lastname: Cang
authors.affiliation: 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;
authors.forename: Sharon
authors.initials: S
authors.lastname: Boast
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Hélène
authors.initials: H
authors.lastname: Thibault
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.affiliation: 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.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Goff
authors.affiliation: 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.
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
mesh_terms: D000217:Acyltransferases / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002135:Calcium-Binding Proteins / Q000378:metabolism; D009202:Cardiomyopathies / Q000209:etiology*; D002352:Carrier Proteins / Q000502:physiology*; D002522:Chlorocebus aethiops; D004452:Echocardiography; D005123:Eye / Q000196:embryology; D054878:Lipoylation; D051379:Mice; D010766:Phosphorylation; D000099211:Phospholamban
chemical_list: D000217:Acyltransferases; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D000099211:Phospholamban; C464939:Zdhhc16 protein, mouse
keywords: Aph2 gene; cardiac development; eye development; palmitoyl transferase; phospholamban