Activation of the caspase-activated DNase in infection and inflammation: functions and consequences

• Applicant: Professor Dr. Georg Häcker
• Subject Area: Immunology ; Virology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570049400

The caspase-activated DNase (CAD) is an endogenous, nuclear enzyme, which in resting cells is bound and kept inactive by its inhibitor, ICAD. CAD is activated through the cleavage of ICAD by caspases. Caspase-dependent activation of CAD was first described in apoptosis, but CAD has no known essential function in apoptotic cell death. CAD can however also be activated by sub-lethal signals in the apoptosis pathway, and recent results suggest relevant roles for CAD during such sub-lethal signaling: sub-lethally activated CAD can regulate growth behavior, can drive inflammation, can contribute to the immune response, and is a driver of cellular senescence. We have further found that CAD is sub-lethally activated in infection as well as by inflammatory stimuli. Experimental activation of CAD strongly alters cellular transcription and induces substantial changes to nuclear chromatin accessibility. Because CAD is activated in infection, and molecular and biological consequences of infection can be similar to the outcome of CAD activation, we here want to test the hypothesis that CAD contributes to the cellular consequences of infection and inflammation. In the first part of this project, we will use models of direct CAD activation and models of CAD-activation by viral infection/inflammation. In either condition, we will test for the activity and contribution of CAD in introducing epigenetic changes and changes in transcription. Cellular senescence is an increasingly recognized consequence of especially viral infection, and CAD is an essential contributor to many forms of senescence. In the second part of the project, we will therefore pursue the hypothesis that CAD is also required for infection- and inflammation-associated cellular senescence. In the third part of the project, we will test the contribution of CAD to a number of additional features of infection and inflammation. We will test whether CAD contributes to ageing-associated inflammation (‘inflammaging’) and to age-associated changes in chromatin accessibility. We will test the hypothesis that CAD-induced epigenetic changes contribute to trained immunity, a cellular adaptation that enables enhanced responses to subsequent infections. We have obtained preliminary data that CAD contributes to collagen-induced arthritis in mice and will test for CAD activation in the joints of patients with rheumatoid arthritis. It is not intuitive that CAD-mediated DNA-damage has physiological roles, but our data strongly suggest this conclusion. The parallels between CAD-induced molecular and cellular consequences and the reported consequences of various infections are intriguing. CAD is activated by infection. It therefore seems a likely hypothesis that at least some of the consequences of infection are the result of CAD activation, and we wish to test this link with this project.

• DFG Programme: Research Grants