Dan Stetson, Ph.D.

PROFESSOR, IMMUNOLOGY

RESEARCH

Research in the Stetson lab focuses on mechanisms by which cells detect and respond to viral infection. All organisms have viral pathogens, and an ancient and fundamental mechanism for detecting viral infection makes use of sensors that recognize viral nucleic acids. In vertebrates, these sensors coordinate an inducible antiviral response by activating the production of type I interferons (IFNs). While the pleiotropic roles of IFNs have been studied since their discovery over five decades ago, recent advances have allowed us to understand their means of induction and complex regulation at a molecular level.

We are particularly interested in a recently described pathway that detects cytosolic DNA within mammalian cells. This pathway, termed the interferon stimulatory DNA (ISD) response, is analogous to the well-characterized RIG-I and MDA5 RNA helicases that detect RNA. However, the ISD pathway signals activation of the antiviral response through a distinct, still poorly characterized mechanism. One goal of our research is to define the specific signaling cascades of the ISD pathway and, more importantly, to determine why they are different from those activated by viral RNA. Another is to understand the biological relevance of the ISD pathway and its connections to Toll-like receptor mediated nucleic acid detection.

Nucleic acid recognition is the principal strategy of viral detection, yet its very nature raises fundamental questions of self/non-self discrimination because of the abundance of self-derived nucleic acids in all cells. We are developing novel mouse model systems to study how dysregulated nucleic acid detection initiates and precipitates autoimmunity and investigating a new mechanism of autoimmunity caused by excessive activation of cytosolic nucleic acid sensors. Finally, the recent renaissance in our understanding of nucleic acid detection will allow us to revisit a number of long-standing, unanswered questions. One fascinating example is the question of why DNA viruses – but not RNA viruses – cause cancer. This question can now be framed in specific molecular terms, and tools are being developed to probe the interconnections between DNA-activated antiviral responses and tumor suppression.

PUBLICATIONS

1. Crow YJ, Stetson DB. 2021. The Type I interferonopathies, ten years on. Nat Rev Immunol, 2021 Oct 20. doi: 10.1038/s41577-021-00633-9.
2. Maurano M, Snyder JM, Connelly C, Henao-Mejia J, Sidrauski C, Stetson DB. 2021. PKR and the integrated stress response drive immunopathology caused by ADAR1 mutation. Immunity, 54(9):1948-1960. PMCID: PMC8446335. bioRxiv preprint (Dec 1, 2020): https://doi.org/10.1101/2020.11.30.405498
3. Burleigh K, Maltbaek JH, Cambier S, Green R, Gale M, James RC, Stetson DB. 2020. Human DNA-PK activates a STING-independent DNA sensing pathway. Science Immunology, 5(43): pii:eaba4219.
4. Volkman HE*, Cambier S*, Gray EE, Stetson DB. 2019. Tight nuclear tethering of cGAS is essential for preventing autoreactivity. eLife, Dec 6;8. pii: e47491. doi: 10.7554/eLife.47491. PMID: 31808743. *Authors contributed equally.
5. Stetson DB. 2018. Autoimmunity: a new frontier awaits. Current Opinion in Immunology, 55:iii-iv.
6. Crowl JT, Stetson DB. 2018. SUMO2 and SUMO3 redundantly prevent a non-canonical type I interferon response. Proceedings of the National Academy of Sciences, 115(26):6798-6803. PMCID: PMC6042150.
7. Brault MR, Olsen T, Martinez J, Stetson DB*, Oberst A*. 2018. Intracellular nucleic acid sensing triggers necroptosis through synergistic type-I interferon and TNF signaling. Journal of Immunology, 200(8):2748-2756. *Corresponding authors. PMCID: PMC5893403.
8. Crowl JT, Gray EE, Pestal K, Volkman HE, Stetson DB. 2017. Intracellular nucleic acid detection in autoimmunity. Annual Review of Immunology, 35:313-336. PMCID: PMC6435037.
9. Gray EE, Winship D, Snyder JM, Child SJ, Geballe AP, Stetson DB. 2016. The AIM2-like receptors are dispensable for the interferon response to intracellular DNA. Immunity, 45:255-266. PMCID: PMC4988931.
10. Pestal K, Funk CC, Snyder JM, Price ND, Treuting PM, Stetson DB. 2015. Isoforms of the ADAR1 RNA editing enzyme independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity, 43(5):933-944. PMC ID: PMC4654992.
11. Lau L, Gray EE, Brunette RL, Stetson DB. 2015. DNA tumor virus oncogenes antagonize the cGAS-STING DNA sensing pathway. Science, 350(6260):568-571.

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