Squid Rewrite Their Proteins on the Fly, Editing RNA Far Beyond What Other Animals Can Manage

Researchers at the University of California, San Francisco spent time inside the cells of a longfin inshore squid, Doryteuthis pealeii, and came away with a more detailed picture of how far this animal will go to rewrite its own instructions. Their study, published in the journal Cell, examined what happens when the squid edits its RNA, the working copy of a gene that cells read when building proteins.

The process is called ADAR-mediated RNA editing, named for the enzymes that carry it out, adenosine deaminase acting on RNA. Humans and other animals do it too, in a temporary and reversible way. One way to picture it: a recipe is printed, and just before it reaches the baker, raisins are swapped for chocolate chips. The recipe on file stays the same. Coleoid cephalopods, the group that includes squid, octopus and cuttlefish, appear to do this far more extensively than any other animals, and the source describes the gap as not even close.

The team, led by bioscientists at UCSF, focused on the proteome, the full set of roughly 24,000 proteins, to learn what the edits actually change. They mapped nearly 8,000 edit sites across more than 2,000 different proteins, in two tissues: the optic lobe, which handles vision and responding to what is seen, and the gills, a comparatively workaday respiratory organ. The optic lobe makes up a sizable share of the squid's central nervous system, and it showed more frequent and more complex editing. The researchers suggest that cephalopods' strong editing ability and their invertebrate-leading nervous system complexity emerged together. The edits fall in protein-coding sequences, not in the non-coding stretches sometimes called junk DNA. Some even land in the ADAR proteins themselves, which may offer a form of self-regulation.

The breadth of the effects was the biggest surprise. First author Jack Moen, a cellular and molecular scientist at UCSF, told ScienceAlert the team found effects on protein activity, stability, localization and interactions with other proteins, with downstream consequences reaching as far as organelle health. By editing the RNA instructions, he said, the animals can produce proteins with different properties without changing their DNA.

Several findings stood out. Edited proteins changed location, shifting from the outer parts of cells toward the nucleus. Recoding appeared to alter mitochondria, the cell's energy-producing organelles, possibly making squid mitochondria more like human ones: more stable under environmental change and better at recycling themselves. Edits also seemed to affect creatine systems, which could supply bursts of energy for evasive movement or demanding brain activity. And Moen said the team was struck by the potential for new protein sequences: they identified 5,000 short proteins absent from both the reference squid proteome and Swiss-Prot, a gold-standard database covering 14,000 organisms.

Before this work, relatively little was known about what these edits do. Earlier studies had linked them to communication in the central nervous system, perhaps as a response to conditions such as temperature swings. Because the edits happen one base at a time and leave the DNA untouched, they also avoid passing potentially harmful mutations to offspring, which is part of the appeal of the strategy.

Why cephalopods and not other animals? Moen said it comes down partly to the structure of their ADAR enzymes and partly to other reasons that need more research. The theoretical numbers are enormous. Counting all the sites found in the RNA sequencing data, Moen told ScienceAlert, the estimate of possible protein variants comes closer to 10^248, well over 100 orders of magnitude beyond the number of atoms in the Universe.

That figure describes potential, not output. Moen said the numbers describe an enormous potential diversity, and how much of it the animals actually produce remains unknown. That open question is where the research goes next.