Pasparakis, Manolis - B 07

Recognition of cytoplasmic DNA by cGAS triggers strong type I IFN responses that are essential for anti-viral defence. The DNA exonuclease TREX1 degrades cytosolic endogenous DNA to prevent aberrant activation of cGAS-STING-dependent IFN responses. Mutations in TREX1 are associated with type I interferonopathies, including Aicardi-Goutières-Syndrome (AGS), familial chilblain lupus (FCL) and systemic lupus erythematosus (SLE). Trex1-/- mice develop a severe cGAS-STING-dependent autoinflammatory pathology characterised by myocarditis, presence of auto-antibodies and increased expression of interferon stimulated genes (ISG). We found increased cell death in tissues from Trex1-/- mice and hypothesized that cell death induction downstream of cGAS-STING activation could contribute to the pathology. 

Our results showed that genetic knockout of the Z-nucleic acid sensor ZBP1 could not prevent the type I IFN-driven pathology of Trex1-/- mice. Moreover, our unpublished results showed that RIPK3 deficiency could also not prevent or ameliorate the pathology of Trex1-/- mice, arguing against a role of necroptosis. However, our preliminary results suggested that combined inhibition of RIPK3-MLKL-dependent necroptosis and caspase-8 dependent apoptosis profoundly affected the phenotype of Trex1-/- mice, suggesting that caspase-8 critically regulates the cGAS-STING mediated pathology caused by accumulation of cytosolic ‘self’ DNA. Here we aim to study the role of caspase-8 in regulating the pathology of Trex1-/- mice and dissect the underlying mechanisms.

Aberrant recognition of endogenous nucleic acids, caused by mutations affecting metabolism, editing or sensing of ‘self’ DNA or RNA causes type I interferonopathies. Our project aims to elucidate the role of caspase-8 in regulating aberrant activation of cGAS-STING-dependent type I IFN responses by endogenous DNA and the resulting pathologies. Our results will contribute to the better understanding of the mechanisms causing type I interferonopathies and may identify novel therapeutic targets.

For more information about the research, please check Manolis Pasparakis Lab. 

• Center for Molecular Medicine Cologne (CMMC)
• CECAD Cologne
• Institute for Genetics
• SFB 1399
• SFB 1403
• CRC 1607