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Functional Microprotein Characterized in Human Cells

NEW YORK (GenomeWeb) – A team led by investigators at Yale University and the Salk Institute for Biological Studies has identified a functional microprotein in human cells — a puny polypeptide that appears to participate in a pathway that removes the cap from messenger RNAs during the mRNA turnover process.

"Despite how much we know about the human genome, there are still blind spots in the genome discovery algorithms," co-senior author Alan Saghatelian, a genomic medicine researcher at the Salk Institute, said in a statement. "You can sequence the whole human genome and never know a protein, like this one, was there because it's too short and falls below the usual length requirement for gene assignment algorithms."

By combining a liquid chromatography and mass spectrometry-based proteomic analysis on human cell lines with new computational methods, Saghatelian and his colleagues narrowed in on a 7 kiloDalton polypeptide produced from a small open reading frame on the X chromosome that is transcribed into LINC01420/LOC550643 RNA. Their findings, published in Nature Chemical Biology yesterday, revealed a functional role for this microprotein, which was subsequently dubbed "non-annotated P-body dissociating polypeptide," or NoBody.

From immunoprecipitation, gene deletion, cellular localization, and other experiments, the team found evidence that the NoBody microprotein is typically found in so-called P-bodies, where proteins and mRNAs interact during the process of mRNA decay and turnover. There, the group's results suggest that NoBody interacts with proteins that remove the 5' cap from mRNAs during a type of mRNA turnover that takes place through the nonsense-mediated decay pathway.

The microprotein may also influence the number of P-bodies that are available for performing nonsense-mediated decay, the researchers noted, since muted P-body number appeared to rise with muted NoBody expression, while enhanced NoBody levels corresponded to declining P-body numbers in their experiments.

"Our study demonstrates that a newly described microprotein, despite its small size, can perturb cellular [RNA-protein] granules and gene expression," Saghatelian and his co-authors wrote, "suggesting that the continued discovery and functional characterization of microproteins stands to provide new insights into important cellular processes."

For example, the authors noted that thousands of other potential microproteins have been detected in human cells using deep RNA sequencing, ribosome footpinting coupled sequencing, and/or proteomic approaches, hinting that still more functional microproteins might await further investigation. 

"[M]icroprotein-encoding [small open reading frames] constitute a significant fraction of genomes," they wrote. "However, it is unclear how many of these newly discovered [small open reading frames] encode functional microproteins."