Innate Immune Recognition of DNA
The cGAS is an innate immune sensor that detects double-stranded DNA. Detection of foreign DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to pathogen infections. But, there is also a challenging side for the host that how they distinguish the foreign DNA with the much abundant self genome. The presence of self or foreign DNA in the cytoplasm is sensed by eukaryotic cells as a danger signal or a sign of foreign invasion. DNA is introduced into the cytoplasm by the host under bacterial or viral infection, transfection etc. Most of the human cells sense the presence of foreign DNA during infection through the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS). Cyclic GMP-AMP (cGAMP) is a second messenger produced by the cGAS thereby triggers the innate immune responses in our body. This cGAMP binds and activates the adaptor protein STING. DNA normally resides in the nucleus and mitochondria. Its presence in the cytosol serves as a Danger-Associated Molecular Pattern (DAMP) which triggers the immune responses. cGAS is a sensor that can detect the presence of DNA in the cytosol as a DAMP and can induce the production of type I IFN and other cytokines. Nuclear genomic DNA can generate cytoplasmic DNA either by chromosome missegregation or due to nuclear damage leading to the synthesis of ssDNA. The formed ssDNA leaks into the cytoplasm and this ssDNA is degraded by the exonuclease TREX1. Self-DNAs are also sources of activators that initiate type I interferon production through cGAS. The production of type I interferon depicts the activity of innate immune response by the cell. Bak and Bax release the mitochondrial DNA in apoptotic cells and this leaked DNA is detected by cGAS, leading to the production of type I IFN. Detection by cGAS is followed by the activation of STING-IRF3.
The production of type I interferons is inhibited by apoptotic caspases. But how exactly the inhibition happens is still not clear. It blocks the mitochondrial DNA induced cGAS activation. How exactly still not clear. There are some arguments about how it inhibits the activity such as; apoptotic caspases blocks the release of DNA from the mitochondrion. Also says that apoptotic caspases activates the nucleases and thereby degrades the mitochondrial DNA as soon as it leaks out to the cytoplasm. Tfam is a protein important for the stability of mitochondrial DNA. Due to any instability of the Tfam protein, the mitochondrial DNA can be released into the cytoplasm. Mitochondrial DNA leakage may happen also due to infection by a virus or due to aging. The activation of cGAS-STING-IRF3 by the mitochondrial DNA leads to the production of type I IFN. The recognition of self DNA by cGAS will also lead to autoimmune diseases. TREX1 is a cytoplasmic exonuclease that degrades DNA either from self or engulfment. TREX1 is located in the outer membrane of the nucleus. It degrades the leaking DNA from the nucleus. RPA and Rad51 are DNA repair and replication factors, which helps in drawing back the generated single-stranded DNA molecules during repairing of damaged DNA molecules that leak out to the cytoplasm. TREX1 is active in the cells where these factors are knockdown or inactive. It is found that the knock out of RPA and Rad51 leads to accumulation of single-stranded DNA molecules in the cytoplasm that cannot be fully degraded by the TREX1 exonuclease. So the accumulation of self DNAs in the cytosol leads to cGAS activation and thereby production of second messenger cGAMP. This follows inflammatory cytokinin production and type I IFN production ultimately leading autoimmune responses.
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