Mechanisms and applications of immune enzymes

Restriction-modification and CRISPR-Cas are prokaryotic antiviral defense systems with transformative biotechnology and therapeutic applications from cloning to genome editing, molecular diagnostics, vaccine manufacturing, synthetic biology, and beyond. Host-virus conflicts drive the diversification of antiviral systems, resulting in restriction enzymes with an enormous array of nucleotide recognition motifs, and Cas proteins capable of targeting a variety of nucleic acid substrates, directly enabling the myriad technologies into which R-M and CRISPR enzymes have been incorporated.
An ongoing renaissance in our understanding of prokaryotic antiviral immunity has revealed over a hundred new defense systems, most of which are uncharacterized, but which often come in multiple flavors or “types” like R-M and CRISPR-Cas, with their own slightly different functions and potential uses. Taking advantage of bioinformatics, biochemistry, structural biology, and genetics we aim to gain insight into how new systems detect and restrict viral infection, and imagine how the core functions of immune enzymes may be applied to the vast array of problems faced by the biomedical science industry.

While the functions of many new systems remain unclear, an emerging theme amongst some of those which have been better studied is detection of conserved molecular patterns associated with phage infection, and triggering of a cell death response. This altruistic “abortive infection” response blocks production of phage progeny, sparing neighboring isogenic cells which would otherwise be infected by progeny phage. Depicted here is a cyclic oligonucleotide-based antiphage signaling system (CBASS) which is composed of a phage sensor nucleotidyltransferase (pink, PDB: 6E0O) that produces a cyclic oligonucleotide signaling molecule, and an effector enzyme (lavender, PDB: 6VM6) which is activated by this second messenger to drive cell death.