On the TV show “House, MD” one of the mantras was “It’s never lupus.” This was usually said in the context of a patient suffering from symptoms consistent with lupus such as joint and muscle pain, fever, rash, and fatigue. Lupus is an autoimmune disorder. Instead of the immune system attacking foreign pathogens, it turns on itself and beings attacking host cell, specifically the DNA.
Dr. Zhijan James Chen from the HHMI HHMI/UT Soutwestern Medical Center at Dallas is working to understand this debilitating disease. In Dr. Chen’s talk: Enemy within – immune and autoimmune responses to the cytosolic DNA and RNA, he described how he used old school biochemical techniques combined with new biotechnological advancements to understand intracellular DNA sensing.
The first issue to consider was why cells would even have a mechanism for sensing DNA in the cytoplasm to begin with. In healthy cells, DNA is sequestered in the nucleus (and a little on the mitochondria). The presence of DNA in the cytoplasm is a clear sign that something has gone wrong. As Dr. Chen described, one of the advantages to sensing DNA is the versatility: almost all infections utilize it: retroviruses, DNA viruses, bacteria (like tuberculosis), and parasites (like malaria). However, there are rare times when host DNA gets into the cytoplasm such as cell death, defective DNA repair, or damaged mitochondria. When this happens in the cytoplasm of immune cells, it allows for the production of inflammatory cytokines and the beginning of an autoimmune response.
Several times during his talk, Dr. Chen referred to historical perspectives on immunity to give context to his research. First, he opened describing a passage from Dr. Ilya Mechnikov’s Nobel Prize Lecture “On the Present State of the Question of Immunity in Infectious Diseases” that described surgeons delivering “nucleic acid….with the object of bringing to the scene a protective army of phagocytes to ward the microbes off.”
- Figure 1: STING signaling. Modified from Paludan et al.
Even with this historical anecdote, there was a gap in the knowledge of how DNA was sensed in the cytoplasm. Most of the research had focused on STING (Figure 1)- an endoplasmic reticulum protein on the cytosolic side of the ER membrane. This protein was known to stimulate immune cells in response to foreign DNA, but it was unclear how it did so. Dr. Chen described how they were surprised that the activator was not a protein but a small molecule they called cGAMP (2’3’-cAMP-cGMP, Figure 2).
This molecule activates STING in a manner analogous to but mechanistically different from the way cAMP activates protein kinase A. With this discovery, the search turned to identifying the enzyme that synthesizes cGAMP, the cyclic GAMP synthase (cGAS). cGAS not only synthesizes the messenger but also senses the DNA. Dr. Chen and his colleagues demonstrated how cGAS binds DNA in a sequence independent manner, which would be essential for giving it the universality to detect all of the different pathogens mentioned above. However, this also leaves it unable to distinguish between host DNA and foreign DNA.
In addition to lupus, Dr. Chen described how cytoplasmic DNA leads to another disease, Aicardi-Goutieres syndrome, where the absence of the DNA exonuclease TREX1 leads to accumulation of DNA in cells, triggering a painful autoimmune response. In a mouse model of this disease, knocking out the cGAS gene resulted in rescuing the mice, suggesting that inhibiting cGAS would not only be a potential avenue for treating lupus but also this rare but very sever disorder.
To learn more about Dr. Chen and his research, here are some useful links and references (some used within this post):
Dr. Chen’s lab at UT Southwestern Medical Center
DNA sensing and cGAS references
- Paludan and Bowie, 2013, Immunity 38 (5), 870–880
- Sun et al, Science 15 February 2013: Vol. 339 no. 6121 pp. 786-791
- Wu et al, Science 15 February 2013: Vol. 339 no. 6121 pp. 826-830
Diseases