SPEG (Striated Muscle Preferentially Expressed Protein Kinase) Is Essential for Cardiac Function by Regulating Junctional Membrane Complex Activity.
SPEG (Striated Muscle Preferentially Expressed Protein Kinase) Is Essential for Cardiac Function by Regulating Junctional Membrane Complex Activity.
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DOI：
10.1161/circresaha.116.309977
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发表时间：
2017-01-06
影响因子：
20.1
通讯作者：
Wehrens XH
中科院分区：
文献类型：
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作者：
Quick AP;Wang Q;Philippen LE;Barreto-Torres G;Chiang DY;Beavers D;Wang G;Khalid M;Reynolds JO;Campbell HM;Showell J;McCauley MD;Scholten A;Wehrens XH
连接膜复合物（JMC）是心肌细胞中重要的微区，在其中发生兴奋-收缩偶联。JMCs结构和功能的破坏是衰竭心脏收缩功能障碍的基础。然而，新发现的JMC蛋白“横纹肌优先表达基因”（SPEG）的作用尚不清楚。确定SPEG在健康和衰竭成人心脏中的作用。免疫沉淀的JMC-蛋白质Ryanodine受体2型（RyR 2）和junctophilin-2（JPH 2）的蛋白质组学分析，随后通过质谱鉴定的丝氨酸-苏氨酸激酶SPEG作为唯一的新的结合伴侣的两种蛋白质。实时PCR显示，在失败的人类心脏中，SPEG mRNA水平下调。一种新型心肌细胞特异性Speg条件性敲除（MCM-Spegfl/fl）模型揭示，成人发作的Speg缺乏会导致心力衰竭。心力衰竭后MCM-Spegfl/fl小鼠心室肌细胞的钙（Ca 2+）和横小管（TT）成像显示SR Ca 2+火花频率增加，JMC完整性受损。另外的研究表明，在MCM-Spegfl/fl小鼠中，TT破坏先于心力衰竭的发展。尽管总JPH 2水平未改变，但发现MCM-Spegfl/fl小鼠中JPH 2磷酸化水平降低，表明JPH 2的SPEG磷酸化的丧失导致TT破坏，这是SPEG缺陷小鼠中心力衰竭发展的前兆。新的JMC蛋白SPEG在人类衰竭心脏中下调。小鼠心脏中SPEG的急性损失导致JPH 2去磷酸化和TT损失，与下游Ca 2+处理不当相关，导致心力衰竭。我们的研究表明，SPEG可能是治疗心力衰竭的新靶点。
Junctional membrane complexes (JMC) in myocytes are critical microdomains, in which excitation-contraction coupling occurs. Structural and functional disruption of JMCs underlies contractile dysfunction in failing hearts. However, the role of newly identified JMC protein ‘striated muscle preferentially expressed gene’ (SPEG) remains unclear. To determine the role of SPEG in healthy and failing adult hearts. Proteomic analysis of immunoprecipatated JMC-proteins ryanodine receptor type-2 (RyR2) and junctophilin-2 (JPH2) followed by mass spectrometry identified the serine-threonine kinase SPEG as the only novel binding partner for both proteins. Real-time PCR revealed downregulation of SPEG mRNA levels in failing human hearts. A novel cardiac myocyte-specific Speg conditional knockout (MCM-Spegfl/fl) model revealed that adult-onset SPEG-deficiency results in heart failure. Calcium (Ca2+) and transverse-tubule (TT) imaging of ventricular myocytes from MCM-Spegfl/fl mice post heart failure revealed both increased SR Ca2+ spark frequency and disrupted JMC integrity. Additional studies revealed that TT disruption precedes the development of heart failure development in MCM-Spegfl/fl mice. Although total JPH2 levels were unaltered, JPH2 phosphorylation levels were found to be reduced in MCM-Spegfl/fl mice, suggesting that loss of SPEG phosphorylation of JPH2 led to TT disruption, a precursor of heart failure development in SPEG deficient mice. The novel JMC protein SPEG is downregulated in human failing hearts. Acute loss of SPEG in mouse hearts causes JPH2 dephosphorylation and TT loss associated with downstream Ca2+ mishandling leading to heart failure. Our study suggests that SPEG could be a novel target for the treatment of heart failure.