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RNA, in a circle, without a label, can rev immune system, new research suggests

Mammalian cells use a label to distinguish self from non-self circular RNA molecules. Foreign molecules can trigger anti-cancer immune responses.

It's always fun to be able to provide an update to a previous post. In 2017 I wrote about some intriguing research from the laboratory of dermatologist and genome scientist Howard Chang, MD, PhD, that showed that circular RNA molecules play an important and previously unanticipated role in protecting cells from infection by viruses. These circular RNAs are formed when the intervening bits of a messenger RNA (which carries instructions to make proteins) are removed to leave only the coding parts of a gene.

As Chang explained in an email:

Cells are bombarded by outside invaders, and they have evolved sophisticated systems to tell self and foreign nucleic acids apart. Circular RNAs are a recently recognized class of RNAs that is made by human cells, but some viruses also come as circular RNAs. CircRNAs are of particular interest because they seem far more stable than linear RNAs and last for a long time in the body. My lab discovered that human and mouse cells can distinguish foreign and self circular RNAs, and mount a vigorous immune response against the foreign circRNA. 

Now Chang and former postdoctoral scholar Ye Grace Chen, PhD, have learned that the cells rely on a chemical tag appended to the RNA that serves as a kind of authenticity label that differentiates true cellular RNAs from viral knockoffs. They published their findings recently in Molecular Cell.

As Chang explained:

 It turns out that when human cells make circular RNAs, those circular RNAs are tagged with a chemical mark which tells the cell that this is "self" and prevents the innate immune system from reacting to it. 

Chang and Chen found that, by adding the telltale label, they could help foreign-made RNAs evade the immune system-- an advance that could help researchers modulate gene expression in living cells. Conversely, injecting mice with unlabeled circular RNAs amped up the immune response to an anti-tumor vaccine and extended the lifespan of tumor bearing animals.

"I was surprised by the potency of the anti-tumor activity," said Chang. "I thought maybe we'd have to tinker with the system quite a bit to see any effect, but the effect was clear from the beginning."

Now the researchers are doing a deep dive to better understand the molecules' effects on mammalian cell biology.

"Our work so far taught us that the topology of the RNA -- its circular shape -- can directly communicate with the immune system," Chang said. "Now we're curious about whether and how the specific sequences within these circular RNAs provide other new kinds of instruction for the cell." 

Somehow I have a feeling this particular topic will be rolling around to this blog again someday soon...

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