ATP1B1

ATP1B1 encodes the β1 subunit of the Na+/K+-ATPase and additionally operates as a positive regulator of antiviral innate immunity. Its expression is induced by both DNA and RNA virus infection, whereupon it binds TRAF3 and TRAF6 and potentiates their ubiquitination to drive TAK1 and TBK1 phosphorylation, amplifying type I interferon and proinflammatory cytokine output and restricting viral replication (PMID:34011520). A core arm of this activity is stabilization of TRAF6: ATP1B1 suppresses K48-linked ubiquitination of TRAF6 to sustain NF-κB-dependent inflammatory signaling, a function targeted by the viral protein PRRSV nsp6, which competes for ATP1B1 at residue Leu3 to disrupt the ATP1B1–TRAF6 complex and promote TRAF6 proteasomal degradation (PMID:41252779). Beyond immunity, ATP1B1 physically interacts with DCF1 through asparagine 266, and this interaction in astrocytes modulates structural plasticity and glutamate release via P38 signaling (PMID:29337145). ATP1B1 expression is controlled at multiple levels, including promoter hypermethylation that silences it in renal cell carcinoma downstream of VHL loss (PMID:24452105) and a 3'UTR T-rich polymorphism that governs alternative polyadenylation in human kidney (PMID:24098465). Overexpression raises ATPase activity and suppresses proliferation of gastric carcinoma cells (PMID:18630675), but a unified link between its pump function and its signaling roles has not been characterized in the available corpus.

1. 2008 Low

   Established an early functional readout linking ATP1B1 levels to ATPase activity and growth control, before any signaling role was known.

   Evidence Plasmid overexpression with ATPase activity and MTT proliferation assays in gastric carcinoma cells

   PMID:18630675

   Open questions at the time

   • Single overexpression experiment with no pathway placement
   • Does not distinguish pump activity from other effects on proliferation
2. 2011 Low

   Identified ATP1B1 as a host target of a viral protein, hinting at relevance to infection biology before its immune function was defined.

   Evidence Yeast two-hybrid screen with pull-down and co-localization for HCMV UL136 interaction

   PMID:22030864

   Open questions at the time

   • No functional consequence of the UL136 interaction tested
   • Interaction not validated by reciprocal endogenous methods
3. 2013 Medium

   Showed ATP1B1 expression is regulated post-transcriptionally, defining how a 3'UTR polymorphism tunes mRNA isoform abundance.

   Evidence In vitro polyadenylation assays and RT-PCR isoform quantification in human kidney with genetic association

   PMID:24098465

   Open questions at the time

   • Functional consequence of altered polyadenylation on protein output not established
   • No link to any physiological or disease phenotype
4. 2014 Medium

   Defined an epigenetic control mechanism, placing ATP1B1 silencing downstream of VHL loss in renal carcinoma.

   Evidence Methylation analysis, VHL shRNA knockdown, and demethylating-agent rescue in RCC cell lines and tissues

   PMID:24452105

   Open questions at the time

   • Mechanism linking VHL loss to promoter methylation not resolved
   • Functional role of ATP1B1 loss in tumor progression not tested
5. 2018 Medium

   Revealed a neuronal/glial role by mapping the DCF1 interaction interface and connecting it to astrocyte plasticity.

   Evidence IP-MS, co-IP, Asn266 mutagenesis, and Dcf1 knockout mouse with P38 pathway readouts

   PMID:29337145

   Open questions at the time

   • How the DCF1 interaction couples to P38 mechanistically not resolved
   • Relationship to pump function or immune function unclear
6. 2021 Medium

   Defined ATP1B1's core antiviral signaling function, answering whether it actively shapes innate immunity rather than acting only as a pump subunit.

   Evidence shRNA knockdown, overexpression, reciprocal co-IP, ubiquitination and phosphorylation assays, and viral replication assays

   PMID:34011520

   Open questions at the time

   • Whether enzymatic pump activity is required for signaling not addressed
   • Direct vs. scaffold role in TRAF ubiquitination not dissected
   • Single lab
7. 2024 Low

   Broadened the interactome to suggest involvement in translation and posttranslational processing in alveolar epithelial cells.

   Evidence Co-IP mass spectrometry with PRM validation of candidate interactors in A549 cells

   PMID:38912441

   Open questions at the time

   • No functional follow-up for individual interactions
   • Interactions not validated as direct or functionally consequential
8. 2025 Medium

   Resolved the molecular basis of viral evasion by showing nsp6 competes at Leu3 to destabilize TRAF6, mechanistically extending the antiviral model.

   Evidence Co-IP, ubiquitination assay, nsp6 L3S mutagenesis, and recombinant virus rescue

   PMID:41252779

   Open questions at the time

   • Structural detail of the Leu3 interface not resolved
   • Generalizability beyond PRRSV not tested
9. 2025 Low

   Explored therapeutic targeting of the oncogenic ATP1B1::PRKACA fusion via selective peptide degradation.

   Evidence mRNA-delivered peptide degrader in a preclinical FLC tumor cell model (preprint)

   Open questions at the time

   • Preprint, single study, not peer-reviewed
   • Structural basis of degradation specificity asserted but not validated
   • In vivo efficacy not established

• It remains unknown how ATP1B1's canonical Na+/K+-ATPase pump function relates mechanistically to its TRAF-dependent immune signaling and its DCF1-dependent neuronal roles.
• No reconstitution distinguishing scaffold from catalytic contributions
• No structural model of the TRAF3/TRAF6 interface