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Structural and mechanistic studies of RNA-guided and RNA-targeting antiviral defense pathways

Objective

The evolutionary pressures exerted by viruses on their host cells constitute a major force that drives the evolution of cellular antiviral mechanisms. The proposed research is motivated by our interest in the roles of protein-RNA interactions in both prokaryotic and eukaryotic antiviral pathways and will proceed in two directions. The first project stems from our current work on the CRISPR pathway, a recently discovered RNA-guided adaptive defense mechanism in bacteria and archaea that silences mobile genetic elements such as viruses (bacteriophages) and plasmids. CRISPR systems rely on short RNAs (crRNAs) that associate with CRISPR-associated (Cas) proteins and function as sequence-specific guides in the detection and destruction of invading nucleic acids. To obtain molecular insights into the mechanisms of crRNA-guided interference, we will pursue structural and functional studies of DNA-targeting ribonuceoprotein complexes from type II and III CRISPR systems. Our work will shed light on the function of these systems in microbial pathogenesis and provide a framework for the informed engineering of RNA-guided gene targeting technologies. The second proposed research direction centres on RNA-targeting antiviral strategies employed by the human innate immune system. Here, our work will focus on structural studies of major interferon-induced effector proteins, initially examining the allosteric activation mechanism of RNase L and subsequently focusing on other antiviral nucleases and RNA helicases, as well as mechanisms by which RNA viruses evade the innate immune response of the host. In our investigations, we plan to approach these questions using an integrated strategy combining structural biology, biochemistry and biophysics with cell-based functional studies. Together, our studies will provide fundamental molecular insights into RNA-centred antiviral mechanisms and their impact on human health and disease.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/nucleic acid
  • /natural sciences/biological sciences/microbiology/virology
  • /medical and health sciences/health sciences/infectious disease/RNA virus
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/basic medicine/immunology
  • /natural sciences/biological sciences/molecular biology/structural biology

Call for proposal

ERC-2013-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

UNIVERSITAT ZURICH
Address
Ramistrasse 71
8006 Zürich
Switzerland
Activity type
Other
EU contribution
€ 1 467 180
Principal investigator
Martin Jinek (Prof.)
Administrative Contact
Martin Jinek (Prof.)

Beneficiaries (1)

UNIVERSITAT ZURICH
Switzerland
EU contribution
€ 1 467 180
Address
Ramistrasse 71
8006 Zürich
Activity type
Other
Principal investigator
Martin Jinek (Prof.)
Administrative Contact
Martin Jinek (Prof.)