Molecular mechanisms of nucleic acid recognition
Research
We investigate how the immune system distinguishes self from non-self nucleic acids, focusing on the molecular pathways that maintain immune homeostasis and how their dysregulation drives pathological immune activation. A major line of research centers on the exonucleases TREX1 and TREX2, which contribute importantly to the maintenance of immune homeostasis by degrading endogenous DNA metabolites. We have shown that TREX1, as a tail-anchored protein of the outer nuclear membrane, degrades single-stranded DNA leaking from the nucleus into the cytosol, thereby preventing aberrant activation of the cGAS–STING pathway. Building on these findings, we are are currently exploring the less well-characterized functions of TREX2 in nucleic acid metabolism.
Another focus is on the recognition of RNA by the endosomal sensor TLR7, whose activity is tightly regulated by the chaperone UNC93B1. We have demonstrated that mutations in UNC93B1 cause pathological hyperactivation of TLR7, leading to autoimmunity through erroneous recognition of self RNA. Ongoing work addresses how TLR7–ligand interactions shape receptor activation and how disease-associated TLR7 mutations alter this axis.
By dissecting these pathways, we aim to define the molecular mechanisms underlying defective nucleic acid recognition and to gain novel insights into the pathophysiology of rare childhood autoimmune diseases.
Group members
Collaborative networks
TRR237
DZKJ
Selected publications
Mishra, H., Schlack-Leigers, C., Lim, E.L., Thieck, O., Magg, T., Raedler, J., Wolf, C., Klein, C., Ewers, H., Lee-Kirsch, M.A., Meierhofer, D., Hauck, F., Majer, O., 2024. Disrupted degradative sorting of TLR7 is associated with human lupus. Sci Immunol. 9, eadi9575. https://doi.org/10.1126/sciimmunol.adi9575
Wolf, C., Lim, E.L., Mokhtari, M., Kind, B., Odainic, A., Lara-Villacanas, E., Koss, S., Mages, S., Menzel, K., Engel, K., Dückers, G., Bernbeck, B., Schneider, D.T., Siepermann, K., Niehues, T., Goetzke, C.C., Durek, P., Minden, K., Dörner, T., Stittrich, A., Szelinski, F., Guerra, G.M., Massoud, M., Bieringer, M., De Oliveira Mann, C.C., Beltrán, E., Kallinich, T., Mashreghi, M.-F., Schmidt, S.V., Latz, E., Klughammer, J., Majer, O., Lee-Kirsch, M.A., 2024. UNC93B1 variants underlie TLR7-dependent autoimmunity. Sci Immunol. 9, eadi9769. https://doi.org/10.1126/sciimmunol.adi9769
Günther, C., Wolf, C., Fennen, L., Rösing, S., Beissert, S., Aringer, M., Lee-Kirsch, M.A., 2023. Case Report: Response of cutaneous lupus lesions in SLE to interferon receptor blockade parallels reduction of interferon score in blood. Front Immunol. 14, 1253279. https://doi.org/10.3389/fimmu.2023.1253279, open access
Wolf, C., Fischer, H., Kühl, J.-S., Koss, S., Jamra, R.A., Starke, S., Schultz, J., Ehl, S., Neumann, K., Schuetz, C., Huber, R., Hornung, V., Lee-Kirsch, M.A., 2023. Hemophagocytic lymphohistiocytosis–like hyperinflammation due to a de novo mutation in DPP9. J Allergy Clin Immunol. 152, 1336-1344.e5. https://doi.org/10.1016/j.jaci.2023.07.013, open access
Berndt, N., Wolf, C., Fischer, K., Cura Costa, E., Knuschke, P., Zimmermann, N., Schmidt, F., Merkel, M., Chara, O., Lee-Kirsch, M.A., Günther, C., 2022. Photosensitivity and cGAS-dependent IFN-1 activation in patients with lupus and TREX1 deficiency. J Invest Dermatol. 142, 633-640.e6. https://doi.org/10.1016/ j.jid.2021.04.037, open access
Wolf, C., Brück, N., Koss, S., Griep, C., Kirschfink, M., Palm-Beden, K., Fang, M., Röber, N., Winkler, S., Berner, R., Latz, E., Günther, C., Lee-Kirsch, M.A., 2020. Janus kinase inhibition in complement component 1 deficiency. J Allergy Clin Immunol. 146, 1439-1442.e5. https://doi.org/10.1016/j.jaci.2020.04.002, open access
Zimmermann, N., Wolf, C., Schwenke, R., Lüth, A., Schmidt, F., Engel, K., Lee-Kirsch, M.A., Günther, C., 2019. Assessment of clinical response to Janus kinase inhibition in patients with familial chilblain lupus and TREX1 mutation. JAMA Dermatol. 155, 342. https://doi.org/10.1001/jamadermatol.2018.5077, open access
König, N., Fiehn, C., Wolf, C., Schuster, M., Cura Costa, E., Tüngler, V., Alvarez, H.A., Chara, O., Engel, K., Goldbach-Mansky, R., Günther, C., Lee-Kirsch, M.A., 2017. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. 76, 468–472. https://doi.org/10.1136/annrheumdis-2016-209841
Wolf, C., Rapp, A., Berndt, N., Staroske, W., Schuster, M., Dobrick-Mattheuer, M., Kretschmer, S., König, N., Kurth, T., Wieczorek, D., Kast, K., Cardoso, M.C., Günther, C., Lee-Kirsch, M.A., 2016. RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat Commun. 7, 11752. https://doi.org/10.1038/ncomms11752, open access
Kretschmer, S., Wolf, C., König, N., Staroske, W., Guck, J., Häusler, M., Luksch, H., Nguyen, L.A., Kim, B., Alexopoulou, D., Dahl, A., Rapp, A., Cardoso, M.C., Shevchenko, A., Lee-Kirsch, M.A., 2015. SAMHD1 prevents autoimmunity by maintaining genome stability. Ann Rheum Dis. 74, e17. https://doi.org/10.1136/annrheumdis-2013-204845, open access