Base-modified nucleotides mediate immune signaling in bacteria

Area of Science:

• Microbiology
• Immunology
• Molecular Biology

Background:

• Cellular immunity relies on signaling pathways from pathogen detection to effector activation.
• Cyclic nucleotides are known signaling molecules, but other messengers in bacterial immunity are less understood.

Purpose of the Study:

• To investigate a novel bacterial antiphage system employing nucleobase modification for immune signaling.
• To identify the specific molecules and mechanisms involved in this newly discovered pathway.

Main Methods:

• Analysis of a bacterial antiphage system involving phage nucleotide kinases and adenosine deaminase.
• Identification of deoxyinosine triphosphates (dITPs) as key signaling molecules.
• Investigation of downstream effector activation and its impact on cellular metabolism.

Main Results:

• A bacterial antiphage system was identified that uses nucleobase modification for immune signaling.
• Phage kinases and adenosine deaminase generate deoxyinosine triphosphates (dITPs) as immune messengers.
• dITP signaling leads to nicotinamide adenine dinucleotide (NAD+) depletion and infected cell death, conferring population-level immunity.
• Phages counteract this by depleting deoxyadenosine monophosphate, the dITP precursor.

Conclusions:

• A novel antiphage signaling pathway based on nucleobase modification has been uncovered.
• Noncanonical nucleotides, specifically dITPs, function as a new class of immune messengers in bacteria.
• This discovery expands our understanding of bacterial defense mechanisms against viral predation.