Anderson Douglas M, Makarewich Catherine A, Anderson Kelly M, Shelton John M, Bezprozvannaya Svetlana, Bassel-Duby Rhonda, Olson Eric N
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Sci Signal. 2016 Dec 6;9(457):ra119. doi: 10.1126/scisignal.aaj1460.
Micropeptides function as master regulators of calcium-dependent signaling in muscle. Sarco/endoplasmic reticulum Ca ATPase (SERCA), the membrane pump that promotes muscle relaxation by taking up Ca into the sarcoplasmic reticulum, is directly inhibited by three muscle-specific micropeptides: myoregulin (MLN), phospholamban (PLN), and sarcolipin (SLN). The widespread and essential function of SERCA across diverse cell types has raised questions as to how SERCA is regulated in cells that lack MLN, PLN, and SLN. We identified two transmembrane micropeptides, endoregulin (ELN) and another-regulin (ALN), that share key amino acids with their muscle-specific counterparts and function as direct inhibitors of SERCA pump activity. The distribution of transcripts encoding ELN and ALN mirrored that of SERCA isoform-encoding transcripts in nonmuscle cell types. Our findings identify additional members of the SERCA-inhibitory micropeptide family, revealing a conserved mechanism for the control of intracellular Ca dynamics in both muscle and nonmuscle cell types.
微小肽在肌肉中作为钙依赖性信号传导的主要调节因子发挥作用。肌浆网/内质网钙ATP酶（SERCA）是一种通过将钙摄取到肌浆网中来促进肌肉松弛的膜泵，它受到三种肌肉特异性微小肽的直接抑制：肌调节蛋白（MLN）、受磷蛋白（PLN）和肌脂素（SLN）。SERCA在多种细胞类型中广泛且重要的功能引发了关于在缺乏MLN、PLN和SLN的细胞中SERCA如何被调节的问题。我们鉴定出两种跨膜微小肽，内调节蛋白（ELN）和另调节蛋白（ALN），它们与其肌肉特异性对应物共享关键氨基酸，并作为SERCA泵活性的直接抑制剂发挥作用。编码ELN和ALN的转录本的分布与非肌肉细胞类型中编码SERCA同工型的转录本的分布相似。我们的研究结果鉴定出了SERCA抑制性微小肽家族的其他成员，揭示了在肌肉和非肌肉细胞类型中控制细胞内钙动态的保守机制。
