Abstract
A recently described G307D variant of the endosomal adaptor protein TOM1 causes severe early-onset multiorgan autoimmunity and combined immunodeficiency. By combining biophysical, biochemical and cell culture experiments, we show that the variant causes a defect in the interaction between TOM1 and TOLLIP, another adaptor protein involved in cargo trafficking and regulation of innate immunity. The G307D variant impairs the ability of TOM1 to reduce TOLLIP phosphatidylinositol 3-phosphate binding, an important regulatory mechanism for cargo trafficking commitment for both proteins. Our experiments using TOM1 G307D patient cells suggested that the variant affects autophagy, seen as an aggravated response to amino acid starvation and accumulation of autophagosomes due to autophagosome-lysosome fusion defect. In addition, inflammatory pathways showed excessive activation in TOM1 G307D patient cells. Our data suggest that the interaction between TOM1 and TOLLIP has a role in the regulation of the human immune system and highlight the importance of fundamental cellular functions, such as cargo trafficking, in controlling immune responses. Our study also provides insights into the caveats of immunomodulatory and stem cell therapies in patients with TOM1 pathogenic variants.