TOM1L2

TOM1L2 is a ubiquitin-recognizing membrane-trafficking adaptor that couples ubiquitinated cargo to clathrin- and ESCRT-associated sorting machinery across endosomal, ciliary, and autophagic compartments (PMID:37019113, PMID:16412388, PMID:37802980). It directly binds K63-linked ubiquitin chains and the BBSome inside cilia, where it is required to retrieve ubiquitinated GPCRs (SSTR3, Smoothened, GPR161); disrupting the TOM1L2–BBSome interaction traps TOM1L2, ubiquitin, and these receptors in the cilium (PMID:37019113). At endosomes, its GAT domain binds Tollip while its C-terminus binds clathrin heavy chain, allowing TOM1L2 to recruit clathrin onto endosomal membranes when co-expressed with Tollip (PMID:16412388). TOM1L2 localizes to MYO6-positive APPL1/RAB5 early signaling endosomes through a complex with MYO6 and GIPC1, and loss of MYO6 disperses these endosomes and reduces AKT phosphorylation and RAC-dependent membrane ruffling, linking the adaptor to growth-factor signaling and to endocytosis during spermiogenesis (PMID:28591580, PMID:31901088). During xenophagy, TOM1L2 serves as an adaptor that recruits Rab41 to damaged xenophagolysosomal membranes and brings in the AAA-ATPase VPS4 for ESCRT-mediated membrane repair, supporting clearance of intracellular bacteria (PMID:37802980). In vivo, Tom1l2 hypomorphic mice show splenomegaly, expanded B- and T-cell populations, impaired humoral responses, and increased infection and tumor susceptibility, indicating a physiological role in immune regulation (PMID:18343975).

1. 2006 Medium

   Established the first molecular interactions of TOM1L2 in endosomal sorting, showing it bridges Tollip and clathrin to mark it as a clathrin-recruiting endosomal adaptor.

   Evidence Co-IP, GST pulldown, and co-expression colocalization defining GAT–Tollip and C-terminal–clathrin interactions

   PMID:16412388

   Open questions at the time

   • Did not define the ubiquitinated cargo handled at endosomes
   • Clathrin recruitment shown only on co-overexpression, not endogenous
   • No structural basis for the GAT–Tollip interface
2. 2006 Low

   Linked TOM1L2 to receptor tyrosine kinase signaling by associating it with Src and PDGF-induced mitogenesis, hinting at a signaling adaptor role.

   Evidence Co-IP, DNA synthesis assays, and overexpression in a study centered on TOM1L1

   PMID:16479011

   Open questions at the time

   • TOM1L2 data secondary to TOM1L1, single Co-IP/overexpression experiment
   • Direct effect of endogenous TOM1L2 on Src signaling untested
   • No mechanistic connection to endosomal function
3. 2003 Medium

   Distinguished TOM1L2 from the paralog TOM1 by showing endofin recruits TOM1 but not TOM1L2 to endosomes, establishing partner specificity within the family.

   Evidence GST pulldown, co-IP, and yeast two-hybrid demonstrating absent endofin–TOM1L2 binding

   PMID:14613930

   Open questions at the time

   • Negative result does not identify TOM1L2's own endosomal recruiter
   • Does not address functional consequences of the divergence
4. 2008 Medium

   Provided the first in vivo loss-of-function evidence, tying TOM1L2 to Golgi-associated trafficking and immune homeostasis.

   Evidence GFP-fusion Golgi colocalization and gene-trap hypomorphic mouse with immunological phenotyping

   PMID:18343975

   Open questions at the time

   • Hypomorph leaves residual function; molecular basis of immune defect undefined
   • Connection between Golgi localization and the immune phenotype not established
5. 2017 Medium

   Placed TOM1L2 on MYO6-dependent APPL1/RAB5 signaling endosomes and connected it functionally to AKT signaling and membrane ruffling.

   Evidence Immunofluorescence colocalization, siRNA depletion of MYO6, AKT phosphorylation and live-cell imaging readouts

   PMID:28591580

   Open questions at the time

   • Direct contribution of TOM1L2 (vs MYO6) to AKT signaling not isolated
   • Cargo sorted at these endosomes not identified
6. 2020 Medium

   Defined a MYO6–GIPC1–TOM1/L2 complex organizing early endosomes during spermiogenesis, extending the endosomal role to a tissue-specific context.

   Evidence Reciprocal co-IP, immunofluorescence, electron microscopy, and Snell's waltzer MYO6 KO mouse

   PMID:31901088 PMID:32412041

   Open questions at the time

   • Phenotypes driven by MYO6 loss; TOM1L2's own requirement not directly tested
   • Golgi/acrosome involvement remains correlative
7. 2023 High

   Identified TOM1L2 as a direct K63-ubiquitin and BBSome binder required to retrieve ubiquitinated GPCRs from cilia, defining a conserved ancestral ESCRT-0-like adaptor function.

   Evidence Reciprocal co-IP, direct binding assays, genetic disruption of the TOM1L2–BBSome interface, live imaging, and Chlamydomonas ortholog loss-of-function

   PMID:37019113

   Open questions at the time

   • Structural basis of simultaneous ubiquitin and BBSome engagement unresolved
   • Whether ciliary retrieval uses the same Tollip/clathrin machinery as endosomes unknown
8. 2023 Medium

   Extended the adaptor role to membrane repair, showing TOM1L2 recruits Rab41 and VPS4 to damaged xenophagolysosomal membranes for ESCRT-mediated repair and bacterial clearance.

   Evidence Confocal imaging, intrabody against bacterial cytolysin, Rab GTPase screen, recruitment and bacterial clearance assays

   PMID:37802980

   Open questions at the time

   • Direct TOM1L2–Rab41 binding interface not structurally defined
   • How damage is sensed to recruit TOM1L2 unknown
9. 2026 Low

   Implicated TOM1L2 in mitochondrial extracellular-vesicle membrane fusion mediating mitochondrial transfer and metabolic rescue after ischemia.

   Evidence In vitro ischemia model, live imaging of mitochondrial fusion, membrane potential assays, Western blot for CRLS1, and functional recovery assays

   PMID:41795421

   Open questions at the time

   • TOM1L2 role inferred from functional outcomes without direct mutagenesis or structural validation
   • Mechanism of TOM1L2-mediated fusion undefined
   • Single-lab, single-paper observation

• How TOM1L2's distinct cargo-recognition and recruitment activities are partitioned and regulated across cilia, endosomes, autophagolysosomes, and mitochondria-related membranes remains unresolved.
• No structural model integrating ubiquitin, BBSome, Tollip, clathrin, and Rab41 binding
• Regulatory inputs selecting among compartments are unknown
• Substrate spectrum beyond named GPCRs uncharacterized