Biology subjects

Falkovich, A. H.

Publications and source records attributed to Falkovich, A. H..

2 recordsLinked to original sources

bioRxiv2026

Conserved catalytic activity of immune TIR domains in animals

The Toll/interleukin-1 receptor (TIR) domain is important for immune signaling across bacteria, plants, and animals. In human innate immunity, TIR domains are known to function as adaptors mediating protein-protein interactions, yet studies in bacteria and plants revealed that TIR domains often act as enzymes that produce immune signaling molecules. Here, we show that TIR domains from evolutionarily diverse animals have conserved active sites, implying that they can function as enzymes. In vitro experiments with animal TIRs show that the TIR domain of several Toll-like receptors (TLRs), including that of human TLR4, can produce cyclic ADP-ribose (cADPR), revealing an enzymatic activity previously unknown for TLR TIRs. We show that production of cADPR is a conserved feature of TIR domains across the animal tree of life, implying a role for this molecule in animal TIR signaling. Finally, we report a TIR domain from green algae that synthesizes 3'cADPR, suggesting conservation of 3'cADPR signaling between bacteria and eukaryotes. Our results reveal that the catalytic activity of TIR domains is widespread in animals and conserved across the tree of life.

immunology↗

bioRxiv2025

Bacteria sense virus-induced genome degradation via methylated mononucleotides

Phages often degrade the genome of their bacterial host to individual nucleotides and use these nucleotides to build their own genome. In this study, we describe a bacterial defense system that directly senses phage-mediated host genome degradation. This system, called Metis, aborts phage infection once it detects the accumulation of the modified mono-nucleotide N-methyl-deoxyadenosine monophosphate (mdAMP). As methylation of deoxy adenosines occurs only in the context of the DNA polymer, intracellular accumulation of mdAMP serves as a definitive signal that the host genome has been degraded to its individual constituents. In type I Metis, sensing of mdAMP activates an NAD+ diphosphatase, leading to rapid NAD depletion and cessation of the infection process; while the effector in type II Metis is a transmembrane-spanning protein whose toxicity is triggered in response to the modified mono-nucleotide. We further show that Metis defense depends on endogenous DNA methylases, and that phages can escape Metis via mutations that inactivate phage-mediated host genome degradation. Our results demonstrate how molecular byproducts released during virus-induced cell exploitation can be used as specific danger signals that trigger host immunity.

microbiology↗