A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle
By Benjamin R Nelson, Catherine A. Makarewich, Douglas M. Anderson, Benjamin R. Winders, Constantine D. Troupes, Fenfen Wu, Austin L. Reese, John R. McAnally, Xiongwen Chen, E. Kavalali and 4 more. Science, 2016
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Another micropeptide flexes its muscle Genome annotation is a complex but imperfect art. Attesting to its limitations is the growing evidence that certain transcripts annotated as long noncoding RNAs (lncRNAs) in fact code for small peptides with biologically important functions. One such lncRNA-derived micropeptide in mammals is myoregulin, which reduces muscle performance by inhibiting the activity of a key calcium pump. Nelson et al. describe the opposite activity in a second lncRNA-derived micropeptide in mammalian muscle, called DWORF (see the Perspective by Payre and Desplan). This peptide enhances muscle performance by activating the same calcium pump. DWORF may prove to be useful in improving the cardiac muscle function of mammals with heart disease. Science, this issue p. 271; see also p. 226 A long noncoding RNA encodes a small peptide that activates a calcium pump regulating muscle contraction. [Also see Perspective by Payre and Desplan] Muscle contraction depends on release of Ca2+ from the sarcoplasmic reticulum (SR) and reuptake by the Ca2+adenosine triphosphatase SERCA. We discovered a putative muscle-specific long noncoding RNA that encodes a peptide of 34 amino acids and that we named dwarf open reading frame (DWORF). DWORF localizes to the SR membrane, where it enhances SERCA activity by displacing the SERCA inhibitors, phospholamban, sarcolipin, and myoregulin. In mice, overexpression of DWORF in cardiomyocytes increases peak Ca2+ transient amplitude and SR Ca2+ load while reducing the time constant of cytosolic Ca2+ decay during each cycle of contraction-relaxation. Conversely, slow skeletal muscle lacking DWORF exhibits delayed Ca2+ clearance and relaxation and reduced SERCA activity. DWORF is the only endogenous peptide known to activate the SERCA pump by physical interaction and provides a means for enhancing muscle contractility.
Subfields: Cancer Research, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/afbf5ee3b5c380ec69830a2e37e92b9cddf772cd
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Citations in the corpus
- The BIG Data Center: from deposition to integration to translation (2016, background): “Moreover, considering the functional significance of lncRNA-encoded small proteins as reported in (45,46), we developed computational approaches for identification of small proteins in all collected human lncRNAs, identified 9387 lncRNAs potentially encoding small proteins and revealed that 2246 out”
- Long Non-coding RNAs in the Cytoplasm (2016, background): “Interacting directly with SERCA, MLN disrupts the Ca2+ uptake into the sarcoplasmic reticulum [100].”
- Non-coding RNAs in disease: from mechanisms to therapeutics (2023, neutral): “For example, a muscle-specific lncRNA is translated into the 35-amino-acid protein DWORF, which was shown to regulate intracellular calcium signalling in heart tissue 88 .”
- LncRNA-mediated regulation of cell signaling in cancer (2017, background): “…non-coding RNAs (ncRNAs) and they lack the coding potential except for those capable of producing functional small peptides (Anderson et al 2015, Nelson et al 2016). ncRNAs were initially considered as transcriptional noises (Gibb et al 2011), however, it has become increasingly apparent that…”