The Caspase-Activated DNase drives inflammation and contributes to defense against viral infection.
Abdul MoeedNico ThilmanyFrederic BeckBhagya K PuthusseryNoemi OrtmannAladin HaimoviciMohamed Tarek BadrElham Bavafaye HaghighiMelanie BörriesRupert ÖllingerRoland RadSusanne KirschnekIan Edward GentleSainitin DonakondaPhilipp P PetricJonas F HummelElisabeth PfaffendorfPaola ZanettaChristoph SchellMartin SchwemmleArnim WeberGeorg HäckerPublished in: Cell death and differentiation (2024)
Mitochondria react to infection with sub-lethal signals in the apoptosis pathway. Mitochondrial signals can be inflammatory but mechanisms are only partially understood. We show that activation of the caspase-activated DNase (CAD) mediates mitochondrial pro-inflammatory functions and substantially contributes to host defense against viral infection. In cells lacking CAD, the pro-inflammatory activity of sub-lethal signals was reduced. Experimental activation of CAD caused transient DNA-damage and a pronounced DNA damage response, involving major kinase signaling pathways, NF-κB and cGAS/STING, driving the production of interferon, cytokines/chemokines and attracting neutrophils. The transcriptional response to CAD-activation was reminiscent of the reaction to microbial infection. CAD-deficient cells had a diminished response to viral infection. Influenza virus infected CAD-deficient mice displayed reduced inflammation in lung tissue, higher viral titers and increased weight loss. Thus, CAD links the mitochondrial apoptosis system and cell death caspases to host defense. CAD-driven DNA damage is a physiological element of the inflammatory response to infection.
Keyphrases
- cell proliferation
- oxidative stress
- induced apoptosis
- cell cycle arrest
- coronary artery disease
- pi k akt
- cell death
- dna damage
- signaling pathway
- endoplasmic reticulum stress
- dna damage response
- dna repair
- weight loss
- heat shock
- sars cov
- immune response
- microbial community
- transcription factor
- inflammatory response
- tyrosine kinase
- weight gain
- heat stress
- obese patients