TOM1 G307D variant alters interaction with TOLLIP impairing autophagosome-lysosome fusion and regulation of innate immunity

Abstract Our study uncovers for the first time the role of TOM1-TOLLIP interaction in the regulation of the human immune system. A recently described G307D variant in the GAT domain of the endosomal adaptor protein TOM1 causes severe early-onset multiorgan autoimmunity and features of combined immunodeficiency. Through a combination of biophysical, biochemical, and cell culture experiments, we show that the variant causes a defect in the interaction of TOM1 and TOLLIP, another adaptor protein involved in cargo trafficking and regulation of innate immunity. The G307D variant deteriorates the ability of TOM1 to reduce TOLLIP’s phosphatidylinositol 3-phosphate binding, an important regulatory mechanism for cargo trafficking commitment for both proteins. TOM1 G307D patient cells demonstrated aberrant autophagy manifested as an aggravated response to amino acid starvation and an autophagosome-lysosome fusion defect leading to accumulation of autophagosomes. Key inflammatory pathways showed exaggerated activation in TOM1 G307D patient cells, providing a plausible explanation for the patients’ phenotype. Our data highlight the importance of fundamental cellular functions such as cargo trafficking in the regulation of the human immune system and provide insights into the caveats of immunomodulatory and stem cell therapies in patients with TOM1 pathogenic variants.