PT  - JOURNAL ARTICLE
AU  - Gal Ofir
AU  - Ehud Herbst
AU  - Maya Baroz
AU  - Daniel Cohen
AU  - Adi Millman
AU  - Shany Doron
AU  - Nitzan Tal
AU  - Daniel B. A. Malheiro
AU  - Sergey Malitsky
AU  - Gil Amitai
AU  - Rotem Sorek
TI  - Antiviral activity of bacterial TIR domains via signaling molecules that trigger cell death
AID  - 10.1101/2021.01.06.425286
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.06.425286
4099  - http://biorxiv.org/content/early/2021/01/06/2021.01.06.425286.short
4100  - http://biorxiv.org/content/early/2021/01/06/2021.01.06.425286.full
AB  - The Toll/interleukin-1 receptor (TIR) domain is a canonical component of animal and plant immune systems. In plants, intracellular pathogen sensing by immune receptors triggers their TIR domains to generate a molecule which is a variant of cyclic ADP-ribose (v-cADPR). This molecule is hypothesized to activate plant cell death via a yet unresolved pathway. TIR domains were recently also shown to be involved in a bacterial anti-phage defense system called Thoeris, but the mechanism of Thoeris defense remained unknown. In this study we report that phage infection triggers Thoeris TIR-domain proteins to produce an isomer of cyclic ADP-ribose. This molecular signal activates a second protein, ThsA, which then depletes the cell of the essential molecule nicotinamide adenine dinucleotide (NAD) and leads to abortive infection and cell death. We further show that similar to eukaryotic innate immune systems, bacterial TIR-domain proteins determine the immunological specificity to the invading pathogen. Our results describe a new antiviral signaling pathway in bacteria, and suggest that generation of intracellular signaling molecules is an ancient immunological function of TIR domains conserved in both plant and bacterial immunity.Competing Interest StatementR.S. is a scientific cofounder and consultant of BiomX Ltd., Pantheon Ltd., and EcoPhage.