Role of ATG16L1 in coordinating DNA damage induced inflammation and tumorigenesis in the intestinal epithelium

Doctoral Researcher

Principal Investigator

Associated Principal Investigator

Background and current state of research

ATG16L1, an autophagy gene with not only autophagy related functions, is known as a risk gene for inflammatory bowel disease.[1] It is not completely understood how ATG16L1 participates in this disease. Previous work of the group indicates, that there is a link between ATG16L1 and the cGAS/STING pathway.

The cGAS/STING pathway is producing Interferon in response to double strained DNA in the cytosol. dsDNA is sensed in the cytosol by cGAS, this enzyme produces cGAMP which activates STING, further TBK-1/IRF3 are activated and this results in the production of type I Interferons. The occurrence of dsDNA in the cytosol can have many reasons. For example trough viral or bacterial infection of the cell or trough DNA damage, which is a result of chronic inflammation.[2]

 

[1] Fowler, Elizabeth V., et al. "ATG16L1 T300A shows strong associations with disease subgroups in a large Australian IBD population: further support for significant disease heterogeneity." The American journal of gastroenterology 103.10 (2008): 2519-2526.

[2] Chen, Qi, Lijun Sun, and Zhijian J. Chen. "Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing." Nature immunology 17.10 (2016): 1142-1149.

Our goals

Our main goal is to verify and understand the linkage of ATG16L1 and the cGAS/STING Pathway. After we have done this we will probably enlarge our horizon by having a closer look on the interaction between ER-Stress and autophagy in the condition of DNA damage.

How to get there

For the in vivo experiments we will do basal phenotyping  and develop a genetical model for chronic DNA damage and activation of the cGAS/STING pathway.[1][2]

For the in vitro experiments we will work mostly with ModeK Cells, in which we will knockout ATG16L1 and stimulate them with different DNA damage inducing drugs, dsDNA and others.

As a more complex in vitro model, we will also derive intestinal organoids, for further experiments.

 
[1] Hiller, Bjoern, Achleitner et. al. Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity. Journal of Experimental Medicine 2012, Volume 209 (8), Pages 1419-1426

[2] Pokatayev, Vladislav, et al. "RNase H2 catalytic core Aicardi-Goutières syndrome–related mutant invokes cGAS–STING innate immune-sensing pathway in mice." Journal of Experimental Medicine (2016): jem-20151464.