Jungsan Sohn

Research Interests
We are interested in understanding mechanisms that allow biological stress-sensors to detect danger signals and initiate highly coordinated coping-responses by assembling into higher order molecular assemblies.

Innate immunity is the first line of defense against invading pathogens in all organisms. The central players of innate immunity are pattern-recognition receptors (PRRs) that can recognize molecular patterns associated with pathogens.  A major problem with this strategy is that the danger signals from pathogens are often universal to all organisms such as DNA and RNA!
Two major goals of our research are to determine:

1. How innate immune receptors distinguish self from nonself.
2. How pathogen signals are faithfully transduced by the sequential assembly of supra-structures.

Human absent-in-melanoma-2-like-receptors (ALRs). ALRs are essential intracellular foreign-DNA receptors and play key roles in defense against a number of pathogens such as herpes simplex virus-1 and F. tularensis.  ALRs directly assemble into filamentous supra-structures on foreign-dsDNA. These large multimeric structures, which are dubbed as the inflammasomes, activate the pro-inflammatory caspase-1 protease via the central hub protein named ASC. Activated caspase-1 then executes various host responses including cytokine maturations and cell death (see Fig). 

ALRs are essential in defense against virtually all pathogens that use DNA as genetic materials. However, a growing body of evidence indicates that ALRs have key roles in promoting a number of human diseases including several types of cancer (e.g. prostate cancer, breast cancer, and melanoma) and autoimmune disorders (e.g. Sjögren’s syndrome, systemic lupus erythematosus, and systemic sclerosis).

Mechanistic Biophysics. We weave several classic and cutting-edge biophysical methods in a highly synergistic fashion to resolve the following fundamental mechanistic questions in understanding how ALR-pathways operate at the molecular level:

1. What are the mechanisms by which ALRs selectively and efficiently assemble their signaling platforms on foreign-, but not self-dsDNA?
2. How do ALR propagate foreign-dsDNA signals via inducing the polymerization of downstream ASC?

Selected Publications:  

1. Morrone, SM, Wang, T, Constantoulakis, LM, Hooy, RM, Delannoy, MR, and Sohn, J. Cooperative assembly of IFI16 filaments on dsDNA provides insights into host defense strategy.  PNAS. 2014; 111, E62-71
2. Geertsma, HJ, Schute, AC, Spenkelink, LM, Mcgrath, WJ, Morrone, SR, Sohn, J, Mangel, WF, Robinson, A, van Oijen, A. Single-molecule imaging at high fluorophore concentrations of Dye (LaDYe). Biophysical Journal.  2015; 108, 949-56.  Role: data analysis and manuscript writing
3. Baer AN, Petri MA, Sohn J, Rosen A, Casciola-Rosen L. Antibodies to human IFI16 are present in systemic lupus and primary Sjögren’s syndrome with similar frequencies but detect different parts of molecule. Arthritis Care Res.  2016; 68(2): 254-60 Role: data analysis and manuscript writing
4. Morrone SM, Matyszewski M, Yu, X, Delannoy M, Egelman, EH, and Sohn J. Assembly driven activation of the AIM2 inflammasome provides a template for the polymerization of downstream ASC. Nature Communications. 2015; 6, 7827.
5. Stratmann, S, Morrone, SM, van Oijen AM*, and Sohn J*. The innate immune sensor IFI16 recognizes foreign DNA in the nucleus by scanning along the duplex. eLife. 2015; e11721 *: co-corresponding authors.
6. Matyszewski M, Morrone SM, and Sohn J. Digital signaling network drives the assembly of the AIM2-ASC inflammasome. PNAS. 2018; 115: E1963-72
7. Antiochos B, Matyszewski M, Sohn J, Casciola-Rosen L, and Rosen A. IFI16 filament formation in salivary epithelial cells shapes the anti-IFI16 immune response in Sjögren’s Syndrome. Journal of Clinical Investigation, Insight. 2019; 10. 1172. Role: experimental design, data analysis, and manuscript writing
8. Hooy R.M. and Sohn J. The allosteric activation of cGAS underpins its dynamic signaling landscape. eLife. 2018; e39984
9. Matyszewski M, Zheng W, Lueck J, Antiochos B, Egelman E*, and Sohn J*. The cryo-EM structure of the NLRC4^CARD filament provides insights into how symmetric and asymmetric assemblies are utilized in inflammasome signaling. Journal of Biological Chemistry. 2018; 293 (52) 20240-20248 *: co-corresponding authors.
10. Jian H, Xue X, Panda S, Kawale A, Hooy RM, Liang F, Sohn J., Sung, P, Gekara, NO. Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death. EMBO J. 2019; 38(21) e102718. Role: experimental design, data analysis, and manuscript writing.
11. Hooy RM, Massaccesi G, Rousseau KE, Chattergoon MA, Sohn J. Allosteric coupling between Mn²⁺ and dsDNA controls the catalytic efficiency and fidelity of cGAS.  Nucleic Acids Res.  2020; gkaa084.
12. Crews DC*, Wilson KL*, Sohn J*, Kabacoff CM, Poyton SL, Murphy LR, Bolz J, Wolfe A, White PT, Will C, Collins C, Gauda E, Robinson DN. Helping Scholars Overcome Socioeconomic Barriers to Medical and Biomedical Careers: Creating a Pipeline Initiative. Teach Learn Med. 2020;1-12. *Role: co-first author
13. Matyszewski M, Zheng W, Lueck J, Mazanek Z, Mohideen N, Lau AY, Egelman EH, and Sohn J. Distinct axial and lateral interactions within homologous filaments dictate the signaling specificity and order of the AIM2-ASC inflammasome. Nature Communications. 2021;12, 2735
14. Antiochos B, Trejo-Zamborano D, Fenaroli P, Roseenberg, A, Baer A, Garg A, Sohn J*, Li J, Petri M, Goldman, DW, Mechoi C, Casiola-Rosen, L, and Rosen A, The DNA sensor Aim2 and IFI16 are SLE autoantigens that bind neutrophil extracellular traps. eLife, 2022; 72103. *Role: experimental design/analyses, writing.
15. Garg, A., Stallings, C.M., and Sohn, J. Filament assembly underpins the dsDNA specificity of AIM2-Like Receptors. Nucleic Acids Res. 2023; 51 (6) 2574-2584

16. Wu S, Garg A, Mazanek Z, Belotte G, Zhou JJ, Stallings CM, Lueck J, Roland A, Chattergoon, MA, Sohn, J. Design Principles for Inflammasome Inhibition by Pyrin-Only-Proteins. (2024) eLife, 81918
17. Wu, S, Gabelli, S, and Sohn J. Structural bases for 2’-5’/3’-5’ cGAMP synthase by cGAS (2024) Nature Communications, accepted