ABOVE: A synthetic SINEUP (blue) and its target mRNA (red) colocalize in the cytoplasm as part of a process that appears to help upregulate that mRNA's translation.


The paper
N. Toki et al., “SINEUP long non-coding RNA acts via PTBP1 and HNRNPK to promote translational initiation assemblies,” Nucleic Acids Res, 48:11626–44, 2020.

A few years ago, Piero Carninci of the RIKEN Center for Integrative Medical Sciences in Japan and colleagues discovered a novel type of RNA. These long, noncoding RNAs contain repetitive sequences called short interspersed nuclear elements (SINEs), and they upregulate the translation of specific mRNAs with complementary base sequences. Carninci and colleagues called the RNAs SINEUPs.

Curious about how the upregulation works, the team recently delved into the process using a synthetic SINEUP that targets mRNA coding for green fluorescent protein (GFP). The researchers used plasmids to transfect genes for the synthetic SINEUP and for GFP mRNA into human embryonic kidney cells, and then observed the cells using immunofluorescence microscopy. The two RNA types colocalized in the cytoplasm, suggesting they were interacting, the team found. Using mass spectrometry and small interfering RNA inhibition, the researchers identified two proteins, PTBP1 and HNRNPK, that bind to SINEUP-mRNA complexes and help establish their cellular distribution. The proteins also seem to help initiate translation of the SINEUP-bound mRNA; overexpressing these proteins boosted translation of the target mRNA, Carninci says.

Lynne Maquat, who studies RNA metabolism in human diseases at the University of Rochester Medical Center and was not involved in the work, says the new study is a comprehensive investigation of SINEUP function. But the results of protein overexpression experiments should be interpreted with caution, she says, as they don’t represent natural conditions for the cell, nor do they rule out the possibility that other proteins also play a role in SINEUP-mediated translational regulation. The findings do lay the groundwork for attempts to use synthetic SINEUPs to modify a cell’s production of proteins, she notes.

Carninci, who recently cofounded the biotech TranSINE to translate the research, says the team has therapeutic applications in its sights. “We think we have a mechanism by which we can tune up translation of specific mRNAs,” Carninci says, noting that the approach may hold the potential to treat some rare diseases caused by having only one, instead of the usual two, functional copies of a particular gene. By using a SINEUP to boost translation of the functional gene’s mRNA to double protein output, Carninci says, “we could have drugs that would correct those diseases.”