ATP1B3

ATP1B3 is the β3 subunit of the Na+/K+-ATPase, associating with the catalytic α subunit at cell membranes to support ion-pump assembly and activity (PMID:17176442). Its maturation is governed in the endoplasmic reticulum by CASPR1, which binds the non-glycosylated core form of ATP1B3 (but not the α1 subunit) to drive ATP1B3 glycosylation and plasma-membrane trafficking of the assembled pump; loss of CASPR1 blocks ATP1B3 glycosylation and α1/β3 surface localization, lowering Na+/K+-ATPase activity and impairing glutamate efflux across the blood-brain barrier (PMID:30792309). Beyond ion transport, ATP1B3 acts as an antiviral host factor through several routes: it binds the Enterovirus 71 3A protein and restricts EV71 replication by enhancing type-I interferon production (PMID:27240146), and it restricts hepatitis B virus by activating the NF-κB pathway (P65 phosphorylation and nuclear import) to raise IFN-α, IL-6, and BST-2 levels (PMID:31556466) and, independently of NF-κB, by binding HBV large and medium envelope proteins to drive their polyubiquitination and proteasomal degradation (PMID:33534085). ATP1B3 also serves as a co-factor that accelerates BST-2 degradation and lowers BST-2 surface expression, thereby tuning BST-2-dependent HIV-1 restriction and NF-κB activation (PMID:26694617).

1. 2006 Medium

   Established that ATP1B3 is a bona fide β subunit of the Na,K-ATPase by demonstrating its physical association with the catalytic α subunit at cell membranes, anchoring its canonical ion-transport role.

   Evidence Monoclonal antibody immunoprecipitation and flow cytometry on leukocytes and red blood cell membranes

   PMID:17176442

   Open questions at the time

   • Single Co-IP without structural or stoichiometric detail
   • Functional consequence for pump activity not directly measured
   • Tissue-specific epitope accessibility not mechanistically explained
2. 2015 Medium

   Revealed a non-pump role for ATP1B3 as a co-factor that binds BST-2 and accelerates its degradation, linking ATP1B3 to HIV-1 restriction and NF-κB regulation.

   Evidence Co-immunoprecipitation, siRNA depletion, HIV-1 production and NF-κB reporter assays, BST-2 surface flow cytometry in HeLa cells

   PMID:26694617

   Open questions at the time

   • Molecular mechanism of how ATP1B3 accelerates BST-2 degradation not defined
   • Degradation pathway (proteasomal/lysosomal) not pinned down
   • Single-lab finding
3. 2016 Medium

   Identified ATP1B3 as an antiviral factor against EV71 that binds the viral 3A protein and restricts replication by boosting type-I interferon, broadening its role to direct viral protein engagement.

   Evidence Yeast two-hybrid, siRNA knockdown and overexpression in RD cells with interferon measurement

   PMID:27240146

   Open questions at the time

   • Mechanism linking 3A binding to interferon induction unresolved
   • Interaction not confirmed by reciprocal Co-IP in this entry
   • In vivo relevance untested
4. 2019 High

   Defined the biogenesis pathway of ATP1B3 by showing CASPR1 binds its non-glycosylated core form in the ER to enable glycosylation and pump trafficking, connecting ATP1B3 maturation to blood-brain barrier glutamate efflux.

   Evidence Yeast two-hybrid, GST-pulldown, reciprocal Co-IP, RNAi, immunofluorescence, Na+/K+-ATPase activity and glutamate efflux assays in brain microvascular endothelial cells

   PMID:30792309

   Open questions at the time

   • Structural basis of CASPR1 recognition of core ATP1B3 not resolved
   • Whether CASPR1 acts catalytically or stoichiometrically unknown
   • Generality across non-endothelial cell types untested
5. 2019 Medium

   Showed that ATP1B3 restricts HBV through NF-κB activation, establishing a signaling axis (P65 → IFN-α/IL-6/BST-2) that suppresses viral antigen secretion.

   Evidence Overexpression and shRNA in HepG2 cells, NF-κB Western blots, ELISA for HBsAg/HBeAg, Bay11 pharmacological epistasis

   PMID:31556466

   Open questions at the time

   • Upstream link between ATP1B3 and NF-κB activation not defined
   • Whether pump function is required for signaling unknown
   • Single-lab finding
6. 2021 Medium

   Uncovered a second, NF-κB-independent HBV restriction mechanism in which ATP1B3 directly binds HBV envelope proteins and targets them for proteasomal degradation via polyubiquitination.

   Evidence Co-IP, immunofluorescence co-localization, ubiquitination assay, MG132 rescue, overexpression/silencing in HepG2 cells

   PMID:33534085

   Open questions at the time

   • E3 ligase responsible for polyubiquitination not identified
   • Direct vs. adaptor-mediated ubiquitin transfer unclear
   • Single-lab finding
7. 2025 Low

   Implicated ATP1B3 in glioma cell proliferation and invasion correlated with MAPK and NF-κB pathway activity, while showing it does not directly bind PPP1CA.

   Evidence siRNA knockdown in U87MG/U251MG cells, proliferation/Transwell assays, Western blot of MAPK/NF-κB components, negative PPP1CA Co-IP

   PMID:40027130

   Open questions at the time

   • Pathway placement inferred from Western blot correlation without epistasis
   • Single knockdown approach, single lab
   • Mechanism of indirect PPP1CA regulation undefined

• It remains unknown how ATP1B3's canonical ion-pump function mechanistically connects to its diverse antiviral and signaling activities, and which E3 ligase and upstream signal couple ATP1B3 to ubiquitination and NF-κB.
• No unifying mechanism linking pump role to immune/signaling functions
• E3 ligase and recruitment mechanism for envelope-protein degradation unidentified
• Direct trigger of NF-κB activation by ATP1B3 unresolved