Polypeptide Encoded by Non-Coding RNA Regulates Muscle Regeneration

Their name notwithstanding, long non-coding RNAs (lncRNAs) have been found to actually encode synthesis of small polypeptides that can fine-tune the activity of critical cellular components.

Long non-coding RNAs (lncRNAs) are considered to be non-protein coding transcripts longer than 200 nucleotides. This somewhat arbitrary limit distinguishes lncRNAs from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. LncRNAs have been found to be involved in numerous biological roles including imprinting, epigenetic gene regulation, cell cycle and apoptosis, and metastasis and prognosis in solid tumors. Most lncRNAs are expressed only in a few cells rather than whole tissues, or they are expressed at very low levels, making them difficult to study.

Investigators at Beth Israel Deaconess Medical Center (Boston, MA, USA) reported in the December 26, 2016, online edition of the journal Nature that they had identified and functionally characterized a novel 90 amino acid polypeptide encoded by the lncRNA LINC00961. This polypeptide was found to be conserved between human and mouse, was localized to the late endosome/lysosome, and interacted with the lysosomal enzyme v-ATPase to negatively regulate mTORC1 (mammalian target of rapamycin complex 1) activation. The role of mTORC1 is to activate translation of proteins. The downregulation of mTORC1 by the lncRNA polypeptide was specific to activation of mTORC1 by amino acid stimulation, rather than by growth factors. Therefore they called this polypeptide "small regulatory polypeptide of amino acid response" or SPAR.

The investigators showed that the SPAR-encoding lncRNA was highly expressed in a subset of tissues and used CRISPR/Cas9 engineering to develop a SPAR-polypeptide-specific knockout mouse while maintaining expression of the host lncRNA. They found that the SPAR-encoding lncRNA was downregulated in skeletal muscle upon acute injury. Using this in vivo model, they established that SPAR downregulation enabled efficient activation of mTORC1 and promoted muscle regeneration.

"Whether such small, hidden polypeptides are actually functional, or represent "translational noise" within the cell is still relatively unclear," said senior author Dr. Pier Paolo Pandolfi, director of the cancer center and cancer research institute at Beth Israel Deaconess Medical Center. "Our team set about trying to understand to what extent lncRNA molecules might actually encode functional polypeptides, and how important such peptides might be."

"We are very excited about this discovery," said Dr. Pandolfi. "It represents a new and startling mechanism by which important sensory pathways can be regulated within cells, and we believe it will have important implications for how we approach the design of therapies and treatments in the future."

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Beth Israel Deaconess Medical Center