A TCER-1-siRNA Regulatory Axis Suppresses Antibacterial Innate Immunity in <i>C. elegans</i>

Small interfering RNA (siRNA) are important regulators of gene expression with well-established roles in pathogen defense. Yet, their specific roles in antibacterial immunity are not well understood. Here, we identify an siRNA pathway involved in repressing antibacterial innate immunity in <i>Caenorhabditis elegans</i> . We show that genes required for the biogenesis or function of WAGO Argonaute-associated siRNAs, called 22G-RNAs, function in a common genetic pathway with the immune-suppressive transcription elongation and splicing factor TCER-1 to inhibit immunity. Loss of <i>tcer-1</i> reduced levels of 22G-RNAs from a subset of WAGO targets, while mutations in several WAGO 22G-RNA pathway genes phenocopied the enhanced immunoresistance of <i>tcer-1</i> mutants, suggesting a shared regulatory module. Integrative 22G-RNA-mRNA analyses and molecular genetic studied show that this module does not induce widespread gene silencing, but instead targets a restricted set of immune-relevant effectors, including <i>scrm-4</i> , encoding a phospholipid translocase that promotes host resistance. Together, our findings establish endogenous WAGO 22G-RNAs as repressors of antibacterial immunity and identify TCER-1 as a physiological regulator that promotes 22G-RNA biogenesis to constrain host defense. The results uncover a previously unrecognized small RNA-dependent mechanism linking transcription, metabolism, and antibacterial innate immunity.