TOM1 family proteins: from cargo sorting to immune dysregulation and cancer

Intracellular signaling pathways are modulated by ubiquitin-dependent trafficking, in which specific plasma membrane receptors and cytosolic proteins are tagged, internalized, and degraded in the endolysosomal pathway. Target of Myb1 (TOM1) family proteins, including TOM1, TOM1-L1, and TOM1-L2 function as early adaptors within the ESCRT-0 machinery to recognize ubiquitinated cargo and coordinate its sorting. TOM1 proteins interact with ubiquitin and accessory proteins, such as TOLLIP, facilitating efficient cargo sequestration and endosomal maturation. These interactions are known to be modulated by pathogen-driven processes, such as Shigella flexneri-mediated phosphatidylinositol 5-phosphate accumulation, which can impair TOM1-dependent cargo trafficking. Beyond endosomal sorting, TOM1 contributes to autophagic flux by linking autophagosomes and endosomes through its interaction with the motor protein Myosin VI. Dysregulation of these pathways has been implicated in immune disorders, myocardial ischemia-reperfusion injury, and potentially tumorigenesis. In plants, TOM1-like proteins serve as functional ESCRT-0 analogs, mediating ubiquitin-dependent cargo sorting and integrating stress-responsive signaling. Recent studies have shed light on the modular organization of TOM1, revealing mechanisms of ubiquitin recognition, DXXLL motif function, and complex formation with adaptor proteins. Nonetheless, key questions remain regarding how TOM1 discriminates among ubiquitin linkages, interacts with distinct phosphoinositides under varying physiological conditions, and cooperates with TOLLIP during selective autophagy. Elucidating these mechanisms will advance our understanding of cellular transport and signaling and may reveal novel intervention targets for inflammatory and autoimmune diseases in humans as well as for improving drought tolerance and immune regulation in plants.