ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination

Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) sense microbial ligands and initiate signaling to induce inflammatory responses. Although the quality of inflammatory responses is influenced by internalization of TLRs, the role of endosomal maturation in clearing receptors and terminating inflammatory responses is not well understood. Here, we report that Drosophila and mammalian Vps33B proteins play critical roles in the maturation of phagosomes and endosomes following microbial recognition. Vps33B was necessary for clearance of endosomes containing internalized PRRs, failure of which resulted in enhanced signaling and expression of inflammatory mediators. Lack of Vps33B had no effect on trafficking of endosomes containing non-microbial cargo. These findings indicate that Vps33B function is critical for determining the fate of signaling endosomes formed following PRR activation. Exaggerated inflammatory responses dictated by persistence of receptors in aberrant endosomal compartments could therefore contribute to symptoms of ARC syndrome, a disease linked to loss of Vps33B. [Display omitted] •Loss of Vps33B in flies and macrophages leads to enhanced inflammatory responses•Vps33B is necessary for Drosophila to tolerate non-pathogenic bacteria•Activated TLR4 enters an endosomal trafficking route requiring Vps33B for maturation•High inflammation due to altered endosomes might contribute to symptoms of ARC syndrome Functional mutations in VPS33B gene lead to a fatal human disease called ARC syndrome. Pasare and colleagues demonstrate that activation of PRRs leads to formation of inflammatory endosomes that require Vps33B for maturation. Loss of Vps33B function causes endosomal accumulation of PRRs and their ligands leading to exaggerated inflammatory responses.