Project description
Z-nucleic acids may have therapeutic use as activators of the immune system
DNA or RNA helices usually have a right-handed twist. Under conditions of stress these can also adopt a left-handed zig-zag conformation termed 'Z'. ZBP1 is a sensory molecule that recognizes RNA and DNA in the Z-form. Recognition of Z-nucleic acids by ZBP1 induces antiviral or anticancer immunity, while chronic engagement causes inflammatory pathology. The ERC-funded ZIGNALLING project aims to characterise the molecular mechanisms regulating Z-nucleic acid levels, the biophysical mechanisms of ZBP1 activation and the downstream signaling cascade after ZBP1 activation. Outcomes could lead to therapeutic strategies involving the ZBP1-mediated immune responses.
Objective
Nucleic acids are potent activators of an immune response. Z-nucleic acids are poorly defined and thermodynamically unstable conformers of double-stranded RNA/DNA helices. Recently, others and our group showed that Z-nucleic acids are recognised by the nucleic acid sensor ZBP1, thereby inducing an antiviral immune response. Activation of ZBP1 has also been shown to induce anticancer immunity and it is becoming clear that chronic engagement of ZBP1 by endogenous Z-nucleic acids causes autoinflammatory pathology. On top of that, a remarkably diverse set of cellular insults, ranging from pathogens and chemicals to genetic mutations trigger ZBP1 activation. Despite its relevance in these important (patho)physiological events, knowledge on the fundamental principles that govern Z-nucleic acid-induced ZBP1 signalling is lacking.
I here propose that ZBP1 perceives these widely different disturbances in cellular physiology by detecting the increased intracellular concentrations of Z-nucleic acids. Based on a newly developed ZBP1 activation model and using nanopore sequencing, structural biology and chemical or genetic perturbation methods, we will: (i) characterise the molecular mechanisms that regulate Z-nucleic acid levels, (ii) determine the biophysical determinants of ZBP1 activation, (iii) map the ZBP1 downstream signalling network and (iv) functionally validate our novel findings in cellular and in vivo models of ZBP1 activation.
The resulting detailed mechanistic understanding of ZBP1 function from single molecule to organism will enable us to develop future strategies for therapeutic interference with ZBP1-mediated immune responses, either negatively, to resolve autoinflammation, or positively, to promote antiviral or anticancer immunity.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2023-COG
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9052 ZWIJNAARDE - GENT
Belgium
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