Functionally comparable but evolutionarily distinct nucleotide-targeting effectors help identify conserved paradigms across diverse immune systems

Abstract

While nucleic acid-targeting effectors are known to be central to biological conflicts and anti-selfish element immunity, recent findings have revealed immune effectors that target their building blocks and the cellular energy currency—free nucleotides. Through comparative genomics and sequence-structure analysis, we identified several distinct effector domains, which we named Calcineurin-CE, HD-CE, and PRTase-CE. These domains, along with specific versions of the ParB and MazG domains, are widely present in diverse prokaryotic immune systems and are predicted to degrade nucleotides by targeting phosphate or glycosidic linkages. Our findings unveil multiple potential immune systems associated with at least 17 different functional themes featuring these effectors. Some of these systems sense modified DNA/nucleotides from phages or operate downstream of novel enzymes generating signaling nucleotides. We also uncovered a class of systems utilizing HSP90- and HSP70-related modules as analogs of STAND and GTPase domains that are coupled to these nucleotide-targeting- or proteolysis-induced complex-forming effectors. While widespread in bacteria, only a limited subset of nucleotide-targeting effectors was integrated into eukaryotic immune systems, suggesting barriers to interoperability across subcellular contexts. This work establishes nucleotide-degrading effectors as an emerging immune paradigm and traces their origins back to homologous domains in housekeeping systems.

Altruistic feeding and cell-cell signaling during bacterial differentiation actively enhance phenotypic heterogeneity

“…The calcineurin-like superfamily comprises universally distributed phosphoesterase domains that feature a four-layered α/β sandwich fold formed from two repeat units of the IF3-C domain ( 22 ) ( Fig. 2B - C ).…”

“…It displays 5 conserved motifs that bind two divalent metal ions (usually Zn(II) or Fe(II)) that catalyze phosphoester hydrolysis. Members of this superfamily act on a variety of organophosphate substrates, including nucleic acids, nucleotides, phosphate-containing lipid head groups, and phosphorylated serines and threonines in proteins ( 22 ). Indeed, a B. subtilis member of one clade of calcineurin-like phosphoesterases (PhoD) has been previously shown to degrade the phosphodiester linkages in cell surface teichoic acids that feature glycerol phosphate or ribitol phosphate ( 23 ).…”

het-Ballorecognition inPodospora anserinais determined by pseudo-allelic interaction of genes encoding a HET and lectin fold domain protein and a PII-like protein

“…It is conceivable that the BP PII-like recognizes a small molecule (possibly an adenine nucleotide) acting as a cue of pathogenic challenge and consequently interacts with BH to trigger HET-mediated RCD. Considering the centrality of nucleotide-derived signaling in immune pathways (89, 90), the involvement of a PII-like protein in this allorecognition and RCD system calls for further exploration of its sensing specificity and biological function.…”