Immunity system complexity: DNA hunts pathogens (Introduction)

by David Turell , Sunday, September 22, 2024, 17:13 (62 days ago) @ David Turell

An unusual role involving an enzyme:

https://www.the-scientist.com/dna-sensing-enzyme-wins-the-2024-lasker-award-72188

"...for the discovery of the cGAS enzyme that spots DNA threats from foreign pathogens and self-DNA, caused by cellular stress or damage, in the cytosol. Like the first domino in a chain reaction, its activation sparks a cascade of events, triggering immune and inflammatory responses.

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"DNA is normally contained in the nucleus and mitochondria, so when it shows up where it doesn’t belong—like outside the cell or floating in the cytoplasm—the cell immediately sounds the alarm. Cells have built-in detectors called pattern recognition receptors that sense pathogen- and self-derived threats. Toll-like receptors are one line of defense along the cell surface and endosomes that can detect nucleic acids signaling potential danger. Once the alert goes out, the cell gets busy, cranking out proinflammatory cytokines, chemokines, and type I interferons (IFNs) to rally the troops and take down the pathogen.

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"In 2005, Chen and his team discovered a novel protein called mitochondrial antiviral signaling (MAVS)—which recognized viral RNA—named in homage to its localization on the mitochondria and the Dallas Mavericks. It was one of the first mitochondrial proteins shown to have a direct role in innate immunity. Suppressing MAVS blocked IFN production, making cells vulnerable to viral replication and death. Overexpression, however, conferred antiviral immunity, shielding cells from damage.

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"...independently identified an essential adaptor protein on the endoplasmic reticulum that is involved in DNA sensing. This protein, which Barber named stimulator of interferon genes (STING), mobilized cells to activate the transcription factors nuclear factor-kappa B (NF-κB) and interferon regulatory factor 3 (IRF3) to pump out type I IFNs like interferon beta (IFN-β). Cells missing the STING protein were highly vulnerable to viral infections. Just as MAVS acted as the adapter protein in the RNA pathway, Barber’s group reported STING as the adapter in the DNA pathway. However, despite STING’s importance, it does not directly sense DNA—there was a missing link.

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"The team suspected they had discovered a novel second messenger. Upon further investigation, they found that the molecule was GMP and AMP joined together by two phosphodiester bonds: cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), the first cyclic di-nucleotide in mammalian cells. “This pathway is highly conserved during evolution. It originates in bacteria and is very important for immune defense against bacteriophage infection. cGAS’s antiviral function has been conserved for billions of years from bacteria to humans,” remarked Chen.

"Their findings demonstrated that cytoplasmic DNA, not RNA, set off a chain of events. cGAMP functioned as an endogenous second messenger to activate downstream signaling events that trigger antiviral immunity. However, Chen wanted to figure out the enzyme that made cGAMP.

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"Because cGAS was the only candidate that produced cGAMP activity, this finding solidified its place as the elusive cytosolic DNA sensor to complete the cGAS-cGAMP-STING pathway.

“'It was quite a surprise that this sensor turned out to be an enzyme,” said Chen. “[However], it became very clear after we discovered cGAS [that] it was a very simple and clear mechanism of action.”

"Together, his work established that DNA bound to cGAS directly, changed its conformation, and generated cGAMP to, in turn, prod STING to trigger type I IFN production and elicit an innate immune response.

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"However, this powerful sensor can be a double-edged sword. While DNA is safely tucked away in the nucleus or mitochondria, some conditions result in self-DNA getting into the cytoplasm and inadvertently activating cGAS. Instead of protecting the body’s cells, this pathway has been linked to many different diseases: autoimmune diseases, like lupus and arthritis; inflammatory diseases, like myocarditis; and neurodegenerative diseases, like Parkinson’s disease and Alzheimer’s disease.13–15 “Our own DNA becomes the culprit of these diseases,” said Chen.

"While aberrant expression of cGAS can wreak havoc on the body, Chen and others uncovered cGAS’s importance in immune defense against DNA viruses, bacteria, and even retroviruses like HIV.16 Plus, this small molecule is a very potent immune adjuvant for boosting antibody production in enhanced T cell activation."

Comment: how can a complex system like this develop? Can an evolutionary system based on chance mutations achieve it? I strongly doubt it. It had to be designed. What is amazing is how many different ways the immune system protects us.