Affinage

PPP1R3G

Protein phosphatase 1 regulatory subunit 3G · UniProt B7ZBB8

Length
358 aa
Mass
38.0 kDa
Annotated
2026-06-10
8 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP1R3G is a regulatory targeting subunit of protein phosphatase 1 (PP1) that operates in two distinct biological contexts: glycogen metabolism and cell death signaling (PMID:24264575, PMID:34862394). As a glycogen-targeting (G) subunit in liver and adipose tissue, PPP1R3G directs PP1 to activate glycogen synthase, promoting glycogenesis, accelerating postprandial glucose clearance, and lowering hepatic triglyceride levels; its glycogen-binding domain is indispensable for these metabolic effects (PMID:24264575), and its activity couples glycogen synthesis to systemic lipid metabolism, since its loss reduces adipose glycogen and fat accumulation while raising metabolic rate (PMID:27815211). In a mechanistically separate role, PPP1R3G recruits its catalytic partner PP1γ to complex I of the TNFR1 signaling complex to dephosphorylate inhibitory sites on RIPK1, including serine 25, thereby activating RIPK1 kinase activity and driving apoptosis and necroptosis; a PP1γ-binding-deficient mutant fails to support RIPK1 activation, and Ppp1r3g-deficient mice are protected from TNF-induced systemic inflammatory response syndrome (PMID:34862394). This RIPK1-activating function extends to doxorubicin cardiotoxicity, where PPP1R3G removes a transient p38-imposed phosphorylation brake on RIPK1 to trigger early apoptosis, with activated RIPK1 then promoting cytosolic mitochondrial DNA release and ZBP1/IFN-β-driven amplification of late necroptosis (PMID:41984837). Additional cell-context roles in trophoblast migration via Akt/MMP-9 signaling (PMID:37642261) and in oligodendrocyte precursor differentiation via AMPK-Drp1-dependent mitochondrial dynamics (PMID:40834529) have been reported.

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2013 High

    Established that PPP1R3G is a glycogen-targeting PP1 subunit controlling hepatic glucose handling, answering what cellular function the protein serves.

    Evidence Liver-specific transgenic overexpression, primary hepatocyte glycogen synthase assays, and glycogen-binding-domain deletion mutant in mice

    PMID:24264575

    Open questions at the time
    • Direct biochemical reconstitution of the PPP1R3G-PP1-glycogen synthase complex not shown
    • Identity of the PP1 catalytic isoform engaged in liver not defined here
  2. 2016 High

    Connected PPP1R3G-driven glycogen synthesis to whole-body lipid metabolism, showing its metabolic role extends beyond glucose storage.

    Evidence Whole-body Ppp1r3g knockout mice on high-fat diet with metabolic rate measurement plus 3T3L1 adipocyte overexpression

    PMID:27815211

    Open questions at the time
    • Mechanistic link between glycogen accumulation and triglyceride levels not resolved
    • Tissue-specific contributions (adipose vs liver) not separated genetically
  3. 2021 High

    Revealed a second, signaling role: PPP1R3G recruits PP1γ to dephosphorylate and activate RIPK1, defining it as a positive regulator of TNF-induced cell death.

    Evidence Genome-wide CRISPR knockout screen, PP1γ-binding mutant rescue, RIPK1 S25A epistasis, and Ppp1r3g KO mice in a TNF-induced SIRS model

    PMID:34862394

    Open questions at the time
    • How PPP1R3G is itself recruited to complex I is not defined
    • Full set of RIPK1 inhibitory sites dephosphorylated beyond S25 not enumerated
    • Relationship between the metabolic and cell-death roles unaddressed
  4. 2023 Medium

    Implicated PPP1R3G in trophoblast migration and proliferation through Akt/MMP-9 signaling, extending its roles to cell motility.

    Evidence Lentiviral knockdown in HTR-8/SVneo trophoblasts with wound-healing, Transwell, CCK-8 assays and Akt/MMP-9 western blotting

    PMID:37642261

    Open questions at the time
    • Single lab with no rescue or mutagenesis validation
    • Whether the effect requires PP1 binding is untested
    • Direct link between PPP1R3G and Akt phosphorylation not established
  5. 2025 Medium

    Linked PPP1R3G to oligodendrocyte precursor differentiation via an AMPK-Drp1 axis controlling mitochondrial fission.

    Evidence Ppp1r3g KO mice and primary OPC culture with TEM, RNA-seq, mitochondrial functional assays, and AMPK-activation rescue

    PMID:40834529

    Open questions at the time
    • Biochemical link between PPP1R3G and AMPK not reconstituted
    • Single lab; PP1-dependence of the effect untested
    • How a glycogen/PP1 subunit modulates AMPK activity is unexplained
  6. 2026 High

    Extended the RIPK1-activating function to doxorubicin cardiotoxicity and defined a feed-forward amplification loop, showing PPP1R3G drives both apoptosis and necroptosis in vivo.

    Evidence Ppp1r3g KO mice in a doxorubicin cardiotoxicity model with cell death assays, mtDNA release assays, and ZBP1/IFN-β pathway analysis

    PMID:41984837

    Open questions at the time
    • Whether PP1γ recruitment mediates the cardiac effect not directly tested here
    • Trigger that recruits PPP1R3G after p38 phosphorylation not defined
    • Therapeutic relevance of targeting PPP1R3G not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single PP1 targeting subunit is partitioned between glycogen metabolism and RIPK1-dependent cell death, and what determines its context-specific engagement, remains unresolved.
  • No unifying model linking glycogen-targeting and RIPK1-regulating functions
  • No structural model of PPP1R3G complexes
  • Regulation of PPP1R3G expression and localization across tissues uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
Complex memberships
PP1 holoenzymeTNFR1 signaling complex (complex I)

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 PPP1R3G functions as a glycogen-targeting subunit (G subunit) of protein phosphatase 1 (PP1) in liver, where it stimulates glycogen synthase activity and promotes hepatic glycogenesis. Liver-specific overexpression increases hepatic glycogen accumulation, accelerates postprandial blood glucose clearance, and reduces hepatic triglyceride levels. The glycogen-binding domain of PPP1R3G is indispensable for its effects on glucose metabolism and triglyceride accumulation. Liver-specific transgenic mouse overexpression, primary hepatocyte assays, glycogen synthase activity measurement, domain deletion (glycogen-binding domain mutant) Molecular endocrinology (Baltimore, Md.) High 24264575
2016 Whole-body deletion of PPP1R3G reduces glycogen deposition in adipose tissue, decreases fat accumulation, and increases metabolic rate in high-fat diet-fed mice, linking PPP1R3G-mediated glycogen synthesis to lipid metabolism. In 3T3L1 cells, PPP1R3G overexpression increases both glycogen and triglyceride levels. Whole-body PPP1R3G knockout mouse model, high-fat diet feeding, metabolic rate measurement (O2/CO2), 3T3L1 cell overexpression assays Molecular and cellular endocrinology High 27815211
2021 PPP1R3G recruits its catalytic subunit PP1γ to complex I (TNFR1 signaling complex) to dephosphorylate inhibitory phosphorylation sites on RIPK1 (including serine 25), thereby activating RIPK1 kinase activity and promoting apoptosis and necroptosis. A PPP1R3G mutant that cannot bind PP1γ fails to rescue RIPK1 activation. Ppp1r3g-/- mice are protected from TNF-induced systemic inflammatory response syndrome. CRISPR whole-genome knockout screen, PPP1R3G-PP1γ binding mutant rescue experiments, RIPK1 S25A mutation rescue, Ppp1r3g knockout mice with TNF-induced SIRS model Nature communications High 34862394
2023 PPP1R3G knockdown in HTR-8/SVneo trophoblasts decreases p-Akt/Akt expression and reduces MMP-9 levels, inhibiting trophoblast migration, invasion, and proliferation via the Akt/MMP-9 signaling pathway. Lentiviral knockdown, wound-healing assay, Transwell invasion assay, CCK-8 proliferation assay, western blotting for Akt and MMP-9 pathway components Experimental biology and medicine (Maywood, N.J.) Medium 37642261
2025 PPP1R3G deletion in oligodendrocyte precursor cells (OPCs) inhibits OPC differentiation and myelination. Mechanistically, PPP1R3G loss inhibits AMPK, which normally suppresses Drp1 phosphorylation; reduced AMPK activity permits Drp1-mediated mitochondrial fission, disrupting mitochondrial dynamics (reduced length/number, impaired membrane potential and ATP production), thereby impairing OPC differentiation. AMPK activation rescues the fission defects. Ppp1r3g KO mice, primary OPC culture, immunohistochemistry, TEM, RNA-seq, mitochondrial functional assays, AMPK activation rescue experiment International immunopharmacology Medium 40834529
2026 In doxorubicin-induced cardiotoxicity, DOX triggers p38-mediated inhibitory phosphorylation of RIPK1 as a transient brake. PPP1R3G is recruited to dephosphorylate RIPK1, activating it and triggering early-stage apoptosis. Activated RIPK1 promotes cytosolic release of mitochondrial DNA, inducing ZBP1 expression via IFN-β signaling, which amplifies late-stage necroptosis in a feed-forward loop. Ppp1r3g knockout mice are protected from DOX-induced cardiac dysfunction and mortality. Ppp1r3g genetic KO mice, doxorubicin cardiotoxicity model, in vitro cell death assays, cytokine measurement (TNFα, IFN-β, IFN-γ), mtDNA release assay, ZBP1/IFN-β pathway analysis Proceedings of the National Academy of Sciences of the United States of America High 41984837

Source papers

Stage 0 corpus · 8 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Regulation of glucose homeostasis and lipid metabolism by PPP1R3G-mediated hepatic glycogenesis. Molecular endocrinology (Baltimore, Md.) 42 24264575
2021 RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis. Nature communications 33 34862394
2016 Ablation of PPP1R3G reduces glycogen deposition and mitigates high-fat diet induced obesity. Molecular and cellular endocrinology 19 27815211
2023 Decreased PPP1R3G in pre-eclampsia impairs human trophoblast invasion and migration via Akt/MMP-9 signaling pathway. Experimental biology and medicine (Maywood, N.J.) 3 37642261
2024 Corrigendum: Decreased PPP1R3G in pre-eclampsia impairs human trophoblast invasion and migration via Akt/MMP-9 signaling pathway. Experimental biology and medicine (Maywood, N.J.) 1 39790903
2026 PPP1R3G-RIPK1-ZBP1 axis activates early-stage apoptosis and late-stage necroptosis to promote doxorubicin-induced cardiotoxicity. Proceedings of the National Academy of Sciences of the United States of America 0 41984837
2025 PPP1R3G inhibition impairs OPCs differentiation and myelination in aged mice. International immunopharmacology 0 40834529
2025 PPP1R3G Deletion Blocks RIPK1-Mediated Apoptosis and Necroptosis in Doxorubicin-Induced Cardiotoxicity. bioRxiv : the preprint server for biology 0 41040151

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