TENT5 cytoplasmic non-canonical poly(A) polymerases regulate the innate immune response in animals

Innate immunity, the first line of host defense against pathogens, is tightly regulated both transcriptionally and post-transcriptionally. Through global transcriptome and proteome analyses in Caenorhabditis elegans, we uncover a modulation of the expression of secreted innate immunity effector proteins by TENT5, one of a recently described family of cytoplasmic poly(A) polymerases. Direct RNA sequencing revealed that TENT-5 polyadenylates mRNAs with signal peptide-encoding sequences, that are translated at the endoplasmic reticulum. Loss of tent-5 function makes worms more susceptible to bacterial infection. Importantly, we demonstrate that the function of TENT-5 in innate immunity is evolutionarily conserved, as its orthologs, TENT5A and TENT5C are induced during macrophage activation and polyadenylate mRNAs, some of which are of genes orthologous to C. elegans TENT-5 targets. In summary, our study reveals cytoplasmic polyadenylation to be a previously unknown component of the post-transcriptional regulation of innate immunity in animals. Global transcriptomic analysis of L4-stage tent-5-deficient (TENT-5) and wild-type (WT) worms grown on non-pathogenic Escherichia coli strain HB101 (HB) or infected with Staphylococcus aureus NCTC 8325 (SA) for 8 hours. Other tent-5 IDs: F55A12.9, pqn-44. Transcriptomic analysis of bone marrow-derived macrophages (BMDM) treated with LPS for 8h compared to untreated samples.