Non-canonical poly(A) polymerases (ncPAPs) belong to the family of the terminal nucleotidyltransferases (TENTs) and are implicated in a range of physiological processes which they regulate on the post-transcriptional level. In Caenorhabditis elegans, cytoplasmic polyadenylation has been mostly studied in the context of gametogenesis, in which ncPAP GLD-2 elongates the poly(A) tails of many germline mRNAs, thereby promoting their stability. However, cytoplasmic polyadenylation may play a much broader role than previously anticipated. In worms, innate immunity is the main mechanism of host defense against pathogens, and hence it is tightly regulated at both the transcriptional and post-transcriptional levels. Although the role of post-transcriptional regulation of gene expression in innate immunity is well-appreciated, the particular role of cytoplasmic polyadenylation in this process has never been addressed. We show that C. elegans protein TENT-5 (PQN-44) is an active cytoplasmic ncPAP. Global transcriptome and proteome analyses revealed that TENT-5 is involved in the regulation of genes influencing the interaction between C. elegans and bacteria, including many genes encoding secreted proteins with antimicrobial activity. The poly(A) tail profiling by direct RNA sequencing on Nanopores showed that TENT-5 polyadenylates and stabilizes mRNAs with signal peptide-encoding sequences, that are translated at the endoplasmic reticulum. This aligns with TENT-5 localization in the intestine, which in worms serves as one of the major surfaces of host-pathogen interaction, and TENT-5 enrichment at the endoplasmic reticulum. Furthermore, loss of
tent-5 leads to higher susceptibility of mutant worms to infection with pathogenic bacteria. We propose that TENT-5 regulates the stability and modulates the expression of mRNAs that encode secreted proteins that ensures an energy-effective and rapid response to infection. Importantly, the role of TENT-5 in innate immunity is evolutionarily conserved since murine macrophages devoid of TENT5A and TENT5C ncPAPs also exhibit defects in polyadenylation of numerous mRNAs some of which are of genes orthologous to C. elegans TENT-5 targets. Taken together, our data reveal that cytoplasmic polyadenylation of mRNA encoding innate immunity effector proteins by TENT5 is a previously unknown and essential component of the post-transcriptional regulation of innate immunity.