Abstract
Long noncoding RNAs (lncRNAs) are regulatory molecules which have been traditionally considered as “non-coding”. Strikingly, recent evidence has demonstrated that many non-coding regions, including lncRNAs, do in fact contain small-open reading frames that code for small proteins that have been called microproteins. Only a few of them have been characterized so far, but they display key functions in a wide variety of cellular processes. Here, we show that TUNAR lncRNA encodes an evolutionarily conserved microprotein expressed in the nervous system that we have named pTUNAR. pTUNAR deficiency in mouse embryonic stem cells improves their differentiation potential towards neural lineage both in vitro and in vivo. Conversely, pTUNAR overexpression impairs neuronal differentiation by reduced neurite formation in different model systems. At the subcellular level, pTUNAR is a transmembrane protein that localizes in the endoplasmic reticulum and interacts with the calcium transporter SERCA2. pTUNAR overexpression reduces cytoplasmatic calcium, consistent with a possible role of pTUNAR as an activator of SERCA2. Altogether, our results suggest that our newly discovered microprotein has an important role in neural differentiation and neurite formation through the regulation of intracellular calcium. From a more general point of view, our results provide a proof of concept of the role of lncRNAs-encoded microproteins in neural differentiation.
Highlights
Long noncoding RNAs are RNA molecules of more than 200 nucleotides with diverse regulatory roles, which have been long assumed to not code for proteins
Our analysis revealed that TUNAR, a Long noncoding RNAs (lncRNAs) with a role in pluripotency maintenance and neural differentiation, contains a 48-amino acid small-open reading frames (sORFs) conserved across all vertebrates (Figure 1A), that we have named pTUNAR
We describe a novel 48-amino acid lncRNAencoded microprotein, pTUNAR, which is expressed in the central nervous system. pTUNAR defficiency in mouse embryonic stem cells promotes their differentiation towards the neural lineage both in vitro and in vivo
Summary
Long noncoding RNAs (lncRNAs) are RNA molecules of more than 200 nucleotides with diverse regulatory roles, which have been long assumed to not code for proteins. Recent findings indicate that some lncRNAs and other assumed noncoding regions, such as microRNA precursors, introns and untranslated regions (UTRs) of coding transcripts contain small-open reading frames (sORFs) that are translated into bioactive small proteins (Makarewich and Olson 2017; Orr et al, 2020; Peeters and Menschaert 2020). These sORFs have been long ignored mainly due to an arbitrary cut-off of 300 nucleotides set by ORF prediction algorithms. The relevance of the microproteome regulating neuronal processes has not yet been revealed
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