PPP6R1

PPP6R1 (SAPS1) is a conserved regulatory subunit of the PP6 serine/threonine phosphatase holoenzyme that, in partnership with the catalytic subunit PPP6C, directs substrate-specific dephosphorylation across cell division, DNA repair, and immune signaling (PMID:20040490, PMID:31751917). In dividing cells, the PP6 (PPH-6/SAPS-1) complex governs spindle positioning by controlling cortical actomyosin contractility and by negatively regulating Aurora A kinase localization at the cell cortex, with downstream effects on cortical recruitment of NuMA and dynein (PMID:20040490, PMID:27335426). In the DNA damage response, PPP6R1 is the regulatory subunit that mediates recognition of DNA-PKcs and is required for timely dephosphorylation of γH2AX, p53, and Kap1 after ionizing radiation; its loss renders cells and mice radiosensitive (PMID:31751917). PPP6R1 also functions in immune and cell-death signaling: it exerts negative control over NF-κB signaling and, through interaction with Slfn2, dampens type I IFN-induced NF-κB activation and interferon-stimulated gene expression (PMID:28620030, PMID:29866656). Acting redundantly with PPP6R2 and PPP6R3, PPP6R1 tunes RIPK1-dependent PANoptosis by promoting pro-death RIPK1 S166 autophosphorylation while reducing pro-survival S321 phosphorylation (PMID:38807188). PP6 containing PPP6R1 additionally binds the PB1 and PB2 subunits of the influenza A virus RNA-dependent RNA polymerase and positively supports viral RdRP activity (PMID:25187537). PPP6R1 is expressed at especially high levels in hematopoietic and lymphoid tissues, where its loss disrupts lymphocyte development and signaling (PMID:28620030).

1. 2010 High

   Established that SAPS1/PPP6R1, as a PP6 regulatory subunit, has a cell-division function by linking the PP6 complex to cortical actomyosin organization and spindle positioning.

   Evidence RNAi of pph-6 and saps-1 in C. elegans embryos with live imaging of cortical NMY-2, spindle positioning, and GPR-1/2 and LIN-5 localization

   PMID:20040490

   Open questions at the time

   • Direct phosphatase substrates at the cortex not identified
   • Mechanism by which the complex regulates GPR-1/2 and LIN-5 localization unresolved
   • Conducted in C. elegans embryos; human PPP6R1 contribution inferred
2. 2014 Medium

   Showed that PP6 including PPP6R1 physically engages the influenza A RdRP and positively supports viral replication, extending PP6 function to host-pathogen interaction.

   Evidence Strep-tag affinity purification-MS from infected human cells, direct binding assays with PB1/PB2, and PPP6C siRNA knockdown with viral RNA/growth readouts

   PMID:25187537

   Open questions at the time

   • PPP6R1-specific functional contribution not separated from PPP6C
   • Phosphorylation substrate on the RdRP not defined
   • Direct PPP6R1–PB1/PB2 binding identified by MS without independent confirmation
3. 2016 High

   Defined the Aurora A axis by demonstrating that PP6/SAPS-1 binds and negatively regulates Aurora A cortical localization, placing Aurora A downstream of the complex in spindle positioning.

   Evidence Co-IP of PPH-6/SAPS-1 with AIR-1, acute AIR-1 inactivation and epistasis in C. elegans, plus knockdown and NuMA/dynein imaging in human cells

   PMID:27335426

   Open questions at the time

   • Whether Aurora A is a direct PP6 dephosphorylation substrate not established
   • Cortical dephosphorylation targets controlling NuMA/dynein unknown
4. 2017 Medium

   Connected PPP6R1 to NF-κB-dependent immune signaling and lymphocyte biology, showing tissue-selective high expression and loss-of-function developmental phenotypes.

   Evidence Conditional knockout of PP6c or PPP6R1 in mice with lymphocyte development and NF-κB signaling analyses (perspective summarizing studies)

   PMID:28620030

   Open questions at the time

   • Specific NF-κB pathway substrates of PP6 not identified
   • Single-lab findings summarized in a review
   • Step(s) of NF-κB signaling under PP6 control not fully mapped
5. 2018 Medium

   Provided a molecular partner (Slfn2) through which PPP6R1 restrains type I IFN-induced NF-κB activation and ISG expression.

   Evidence Co-IP of Slfn2 with PPP6R1, Slfn2 knockout mice, and NF-κB activation and ISG expression assays

   PMID:29866656

   Open questions at the time

   • Direct dephosphorylation target downstream of the Slfn2–PPP6R1 interaction not defined
   • Reciprocal validation and structural basis of the interaction not shown
6. 2019 High

   Confirmed PPP6R1 as the substrate-targeting subunit for the DNA damage response, mediating DNA-PKcs recognition and dephosphorylation of repair markers in vivo.

   Evidence SAPS1-null mice, whole-body irradiation survival, clonogenic assays, and dephosphorylation kinetics of γH2AX, p53, and Kap1

   PMID:31751917

   Open questions at the time

   • Direct enzyme-substrate kinetics on individual markers not reconstituted
   • How PPP6R1 recognizes DNA-PKcs structurally not resolved
7. 2020 Low

   Distinguished PP6 (PPH-6/SAPS-1) from PP2A and PP4 in aging host defense and showed the effect is independent of DAF-16/FoxO transcription.

   Evidence RNAi of C. elegans PP6 orthologs in postreproductive adults with pathogen survival assays and DAF-16 reporters

   PMID:33315870

   Open questions at the time

   • Single-lab RNAi with one method per readout
   • Effector pathway downstream of PP6 in host defense unknown
   • Relevance to mammalian PPP6R1 untested
8. 2024 Medium

   Placed PPP6R1 in RIPK1-dependent PANoptosis, showing redundancy with PPP6R2/R3 and a phospho-site-specific influence on RIPK1.

   Evidence CRISPR screen plus individual/combined depletion of PPP6R1/2/3 and PPP6C, with RIPK1 S166 and S321 phosphorylation readouts

   PMID:38807188

   Open questions at the time

   • Whether RIPK1 is a direct PP6 substrate not established
   • Functional redundancy obscures PPP6R1-specific role
   • Single-lab findings

• How a single regulatory subunit, PPP6R1, selects among such diverse substrates (DNA-PKcs/repair markers, Aurora A/cortical factors, NF-κB components, RIPK1, viral RdRP) and is itself spatially and temporally regulated remains unresolved.
• No structural model of PPP6R1 substrate recognition
• Determinants of context-specific substrate targeting unknown
• Direct enzyme-substrate relationships largely inferred rather than reconstituted