The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes

Significance This study identifies a previously undefined role for the inflammatory bowel disease–associated geneRNF186 in innate immunity. RNF186 is expressed in human macrophages and promotes outcomes downstream of receptors responding to microbial products. Upon stimulation of microbial response receptors, RNF186 contributes to assembly and ubiquitination of the signaling complex and subsequent cytokine secretion and antimicrobial pathway induction. Importantly, through different mechanisms, both rare (through impaired ubiquitination) and common (through reduced expression) disease-risk genetic variants inRNF186 lead to a loss in RNF186 function and impaired bacterial clearance in primary human macrophages. These studies highlight a key role for RNF186 in promoting essential innate immune functions contributing to intestinal immune homeostasis.