Protein Trafficking or Cell Signaling: A Dilemma for the Adaptor Protein TOM1

Abstract

Lysosomal degradation of ubiquitinated transmembrane protein receptors (cargo) relies on the function of Endosomal Sorting Complex Required for Transport (ESCRT) protein complexes. The ESCRT machinery is comprised of five unique oligomeric complexes with distinct functions. Target of Myb1 (TOM1) is an ESCRT protein involved in the initial steps of endosomal cargo sorting. To exert its function, TOM1 associates with ubiquitin moieties on the cargo via its VHS and GAT domains. Several ESCRT proteins, including TOLLIP, Endofin, and Hrs, have been reported to form a complex with TOM1 at early endosomal membrane surfaces, which may potentiate the role of TOM1 in cargo sorting. More recently, it was found that TOM1 is involved in other physiological processes, including autophagy, immune responses, and neuroinflammation, which crosstalk with its endosomal cargo sorting function. Alteration of TOM1 function has emerged as a phosphoinositide-dependent survival mechanism for bacterial infections and cancer progression. Based on current knowledge of TOM1-dependent cellular processes, this review illustrates how TOM1 functions in coordination with an array of protein partners under physiological and pathological scenarios.

Keywords: ESCRT; Endofin; TOL; TOLLIP; TOM1; endosome; phosphoinositides.

FIGURE 1

Sequence analysis of the TOM1 family of proteins. Amino acid sequences corresponding to Human TOM1 (accession O60784), TOM1-L1 (accession O75674), and TOM1-L2 (accession Q6ZVM7) were aligned using the Clustal Omega sequence alignment program and reformatted and colored using MView. The boundaries and secondary structure elements of the VHS, GAT, and C-terminal domains for TOM1 are shown in green, salmon, and cyan, respectively.

FIGURE 2

The function of TOM1 in mammals. (A) Cargo is delivered to early endosomes through vesicular transport. TOM1 is recruited by PtdIns3P-bound TOLLIP to these compartments, favoring cargo clustering at maturing endosomes. (B) Endofin recruits TOM1 to early endosomes. Although the function of this complex is unknown, it is possible that it transports cargo for degradation. (C) To mediate amphisome formation, Myosin VI is proposed to bridge endosomal and autophagosomal compartments in coordination with TOM1 and ubiquitinated receptors, which in turn, make contact with the microtubule-associated protein 1A/1B-light chain 3 (LC3) receptors at autophagosomal surfaces. In this proposed model, TOM1 can also make contact with polyubiquitin chains of receptors through VHS and GAT domains. The contact of TOM1 to endosomal surfaces is unknown. TIR, TOM1-interacting region; SBD, Smad-binding domain; RG, reverse gear region; IQ, isoleucine glutamine motif; SAH, single α-helix region; CBD, C-terminal globular cargo-binding domain. (D) Under bacterial infection conditions, PtdIns5P accumulates at signaling endosomes. Ubiquitination processes are subverted by bacterial effectors. PtdIns5P accumulation favors TOM1 sequestration, which promotes ligand-independent receptor-mediated signaling and cell survival.

FIGURE 3

Structural features and binding properties of TOM1 domains. Surface and ribbon representations of the TOM1 VHS (A), GAT (B), and MBM bound to Myosin VI CBD (C). Regions at which ligands bind to the TOM1 VHS and GAT domains are shown. An unresolved structural region in Myosin VI CBD is indicated as a dotted region.