DOP1A

DOP1A (DOPEY1) is a dual-lipid-regulated cargo adaptor that couples organelle membranes to microtubule-based transport: in complex with Mon2 it localizes to the Golgi, endolysosomes, and ER exit sites, where Dopey1 binds PI4P and Mon2 binds phosphatidic acid, and the Dopey1 N-terminus recruits kinesin-1 to drive centrifugally biased bidirectional vesicle transport (PMID:31324769). This trafficking function is required in the nervous system, where loss-of-function causes mislocalization of myelin components — proteolipid protein and myelin-associated glycoprotein accumulate in the oligodendrocyte cell body and myelin basic protein mRNA fails to be properly trafficked — producing impaired oligodendrocyte differentiation and hypomyelination (PMID:24863653, PMID:41067867). Beyond its trafficking role, DOP1A acts in lipid homeostasis at the nuclear envelope: under mTOR control, a shortage of lysophosphatidic acid relocalizes Dop1a to nuclear pore complexes where it binds AGPAT2 to suppress phospholipid synthesis, and its loss elevates phospholipid production, drives nuclear lipid droplet formation, and impairs cell cycle entry through nuclear CDK2 accumulation (PMID:42164854). DOP1A is also co-opted during Helicobacter pylori infection, where CagA-dependent upregulation of DOPEY1 enables it to act with USP7 and TRIP12 to promote p53 degradation (PMID:39939725).

1. 2014 Medium

   Whether DOP1A has a defined cellular function was unknown; a rat loss-of-function model established its role in intracellular trafficking of myelin components in oligodendrocytes.

   Evidence Genetic mapping and nonsense mutation in the VF rat with immunohistochemistry and Western blot for myelin proteins

   PMID:24863653

   Open questions at the time

   • No molecular mechanism for how DOPEY1 mediates myelin component trafficking
   • No identification of binding partners or cargo at this stage
   • Phenotype defined in rat ortholog only
2. 2019 High

   The biochemical basis of DOP1A trafficking activity was undefined; this work established the Dopey1-Mon2 complex as a dual-lipid-regulated cargo adaptor that recruits kinesin-1 to secretory and endocytic organelles.

   Evidence Reciprocal Co-IP, lipid-binding assays, co-localization imaging, organelle fractionation, and functional transport assays

   PMID:31324769

   Open questions at the time

   • Cargo identity for the kinesin-1-driven transport not defined
   • Link between this adaptor mechanism and the myelin trafficking phenotype not directly demonstrated
   • Structural basis of PI4P and PA recognition not resolved
3. 2025 Medium

   Whether DOP1A is co-opted in disease was unknown; H. pylori work placed DOPEY1 upstream of a USP7/TRIP12 axis that degrades p53.

   Evidence LC-MS interactome, reciprocal Co-IP, siRNA knockdown, overexpression rescue, and mouse tumor model

   PMID:39939725

   Open questions at the time

   • Mechanism by which DOPEY1 promotes p53 degradation via USP7/TRIP12 not resolved
   • Relationship between this nuclear/oncogenic role and the cytoplasmic trafficking function unclear
   • Single lab
4. 2025 Medium

   The cellular range of DOP1A in the oligodendrocyte lineage was unclear; expression in OPCs and mature oligodendrocytes was established along with a differentiation/mRNA-trafficking defect.

   Evidence Immunolabeling with lineage markers and Mbp mRNA localization analysis in the VF rat loss-of-function model

   PMID:41067867

   Open questions at the time

   • Molecular link between trafficking machinery and Mbp mRNA localization not defined
   • No in vitro mechanistic reconstitution
5. 2026 Medium

   Whether DOP1A acts in lipid homeostasis beyond vesicle transport was unknown; this work showed mTOR-controlled relocalization to nuclear pore complexes where Dop1a binds AGPAT2 to suppress phospholipid synthesis and safeguard cell division.

   Evidence Live-cell localization, Dop1a-AGPAT2 Co-IP, loss-of-function with lipidomic and cell cycle readouts, and mTOR inhibitor treatment

   PMID:42164854

   Open questions at the time

   • Mechanism of LPA-triggered relocalization to NPCs not resolved
   • How AGPAT2 binding suppresses phospholipid synthesis mechanistically unclear
   • Single lab

• How DOP1A's distinct roles — kinesin-1-coupled membrane transport, nuclear lipid homeostasis, and p53 regulation — are coordinated within one protein remains unresolved.
• No unifying model connecting cytoplasmic adaptor and nuclear functions
• No structural data on domain organization
• Cargo and substrate repertoire incompletely defined