Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy
Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy
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棕榈酰酰基转移酶 Aph2 在心脏功能和心肌病发展中的作用
DOI：
10.1073/pnas.1518368112
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发表时间：
2015-12
影响因子：
11.1
通讯作者：
Li, Baojie
中科院分区：
文献类型：
--
作者：
Thibault, Helene;Scherrer-Crosbie, Marielle;Goff, Stephen P.;Li, Baojie
意义心脏疾病的病因学仍然知之甚少。在本文中，我们首次证明了蛋白质棕榈酰化在心脏结构和功能中起着关键作用。我们证明，Aph 2（嗜磷脂2）是棕榈酰转移酶，并确定受磷蛋白，心肌病基因，作为底物。Aph 2 −/−小鼠的一些心脏缺陷可以通过受磷蛋白消融来挽救。此外，本研究揭示了蛋白质棕榈酰化在胚胎/出生后存活和眼睛发育中的关键作用。蛋白质棕榈酰化调节细胞功能的许多方面，并通过含有zf-DHHC基序的酰基转移酶进行。蛋白质棕榈酰化的体内生理功能在很大程度上是未知的。在这里，我们产生了酰基转移酶Aph 2（亲脂蛋白2或zf-DHHC 16）缺陷的小鼠，并证明了Aph 2在胚胎/出生后存活，眼睛发育和心脏发育中的重要作用。Aph 2-/-胚胎和幼崽表现出心肌病和心脏缺陷，包括心动过缓。我们确定了受磷蛋白，一种经常与人类心肌病相关的蛋白质，作为相互作用的伴侣和Aph 2的底物。Aph 2介导的受磷蛋白半胱氨酸36棕榈酰化差异性地改变了其与PKA和蛋白磷酸酶1 α的相互作用，增强了丝氨酸16磷酸化，并调节受磷蛋白五聚体的形成。Aph 2缺陷导致受磷蛋白磷酸化不足，这是一种超抑制形式。在Aph 2 −/−小鼠中消融受磷蛋白在组织学和功能上减轻了心脏缺陷。这些发现确立了Aph 2作为心脏功能的关键体内调节剂，并揭示了蛋白质棕榈酰化在包括眼睛在内的其他器官发育中的作用。
Significance The etiology of heart disorders remains poorly understood. In this paper, we show for the first time to our knowledge, that protein palmitoylation plays a critical role in heart structure and function. We demonstrate that Aph2 (Ablphilin 2) is a palmitoyl transferase and identify phospholamban, a cardiomyopathy disease gene, as a substrate. Some of the heart defects of an Aph2−/−mouse can be rescued by phospholamban ablation. In addition, the present study reveals critical roles for protein palmitoylation in embryonic/postnatal survival and eye development. 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.
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影响因子：
20.1
作者：
Zhang T;Guo T;Mishra S;Dalton ND;Kranias EG;Peterson KL;Bers DM;Brown JH
通讯作者：
Brown JH
影响因子：
4.5
作者：
Mill P;Lee AW;Fukata Y;Tsutsumi R;Fukata M;Keighren M;Porter RM;McKie L;Smyth I;Jackson IJ
通讯作者：
Jackson IJ
影响因子：
4
作者：
Linder, ME;Deschenes, RJ
通讯作者：
Deschenes, RJ
影响因子：
--
作者：
G. Chu;E. Kranias
通讯作者：
G. Chu;E. Kranias
DOI：
10.1172/jci16738
发表时间：
2003-03
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Qiujing Song;A. Schmidt;H. Hahn;Andrew N. Carr;Beate Frank;L. Pater;Michael J Gerst;Karen B. Young;B. Hoit;B. McConnell;K. Haghighi;C. Seidman;J. Seidman;G. Dorn;E. Kranias
通讯作者：
Qiujing Song;A. Schmidt;H. Hahn;Andrew N. Carr;Beate Frank;L. Pater;Michael J Gerst;Karen B. Young;B. Hoit;B. McConnell;K. Haghighi;C. Seidman;J. Seidman;G. Dorn;E. Kranias