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Cells hack virus-like protein to communicate

Proteins that researchers think are key to long-term memory formation also move genetic material between cells in both mice and flies.
SEM of a fruit fly (drosophila sp.)

A protein in the neurons of flies (Drosophila) is a surprising communicator.Credit: David Scharf/SPL.

The genomes of plants and animals are littered with the remains of viruses that integrated themselves into their DNA hundreds of millions of years ago. Most of these viral remnants are inactive, but the latest research suggests that some evolved into genes that let cells communicate.

A pair of papers1,2 published in Cell on 11 January suggest that the protein encoded by one such gene uses its virus-like structure to shuttle information between cells: a new form of cellular communication that may be key to long-term memory formation and other neurological functions.

Two research groups came across the phenomenon independently while studying extracellular vesicles — pieces of cell membranes that pinch off into bubbles and float away from the cells. These vesicles circulate throughout the body, but little is known about their function. The teams, led by neuroscientist Jason Shepherd at the University of Utah in Salt Lake City and cell biologist Vivian Budnik at the University of Massachusetts Medical School in Worcester, looked at mice and flies (Drosophila melanogaster), respectively.

Protective shells

The researchers found that many of the extracellular vesicles released by neurons contain a gene called Arc, which helps neurons to build connections with one another. Mice engineered to lack Arc have problems forming long-term memories, and several human neurological disorders are linked to this gene.

When Shepherd and Budnik analysed the genetic sequences of mouse and fly versions of Arc, they found that they were similar to that of a viral gene called gag. Retroviruses such as HIV use the Gag protein to assemble protective shells called capsids that transport the virus’s genetic material between cells during infection.

Merged confocal z stacks of NMJ arbors

An SEM of an Arc protein.Credit: J. Ashley et al., Cell 172, 1–13 Jan. 11, 2018. 2017 Elsevier Inc.

When the researchers looked at the Arc protein under a high-resolution microscope, they found that it formed a similar capsid and carried the genetic instructions, or messenger RNA (mRNA), that encode Arc. The capsid was then wrapped in a piece of the cell membrane and released as an extracellular vesicle.

No other non-viral protein has been shown to form capsids and shuttle mRNA between cells. “It’s groundbreaking,” says Clive Bramham, a neuroscientist at the University of Bergen in Norway.

Making connections

In flies, Budnik’s group found that motor neurons — which connect to muscle cells and tell them when to contract — produced vesicles containing Arc. Once the vesicles reached the muscle cells, they fused with those cells’ membranes, releasing the Arc protein and mRNA. It’s unclear what the muscle cell does with the protein and mRNA, but Budnik found that flies that lacked the gene formed fewer connections between neurons and muscles.

Shepherd’s group found a similar phenomenon in neurons taken from mouse brains. Neurons that absorbed extracellular vesicles from other neurons would start using the Arc mRNA to produce the protein once they were stimulated to fire.

Shepherd and Budnik think that the vesicles containing Arc play a part in helping neurons to form and break connections over time as an animal’s nervous system develops or adapts to a new environment or memory. Although the fly and mouse versions of Arc are similar, they seem to have evolved from two distinct retroviruses that entered the species’ genomes at different times. “There must be something really fundamental about it," Budnik says, for it to appear in both mice and flies.

Looking for more

Researchers who study extracellular vesicles are excited by the results, given how little they know about the vesicles’ functions in the body. “This does seem to be something new,” says Kenneth Witwer, a molecular biologist at Johns Hopkins University in Baltimore, Maryland, who studies how HIV interacts with extracellular vesicles.

“This almost raises more questions than it answers,” says Yvonne Couch, a biologist who studies extracellular vesicles at the University of Oxford in the UK. She wonders what stimulates neurons to produce extracellular vesicles and what other material might be carried between neighbouring cells.

Shepherd and Budnik plan to continue studying Arc, but they’re also interested in whether other proteins function in the same way. The human genome contains around 100 gag-like genes that could encode proteins that form capsids. It’s possible that this new form of communication between cells is more common than we thought, Shepherd says. “We think it’s just the beginning.”

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References

  1. 1.

    Pastuzyn, E. D. et al. Cell https://dx.doi.org/10.1016/j.cell.2017.12.024 (2018).

  2. 2.

    Ashley, J. et al. Cell https://dx.doi.org/10.1016/j.cell.2017.12.022 (2018).

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