PPP1R3G

PPP1R3G is a regulatory subunit of protein phosphatase 1 (PP1) that functions in two distinct biological contexts: glycogen metabolism and cell death signaling. As a glycogen-targeting (G) subunit, PPP1R3G recruits PP1 to glycogen particles where it dephosphorylates and activates glycogen synthase, promoting glycogen accumulation in liver and adipose tissue, with downstream effects on triglyceride metabolism (PMID:24264575, PMID:27815211). In TNF-driven cell death signaling, PPP1R3G recruits the PP1γ catalytic subunit to TNFR1 complex I to remove inhibitory phosphorylations from RIPK1 (including Ser25), thereby unleashing RIPK1 kinase activity to drive apoptosis and necroptosis; this mechanism extends to doxorubicin-induced cardiotoxicity, where RIPK1 activation triggers mitochondrial DNA release, IFN-β-mediated ZBP1 induction, and amplified necroptotic signaling (PMID:34862394, PMID:41984837). PPP1R3G additionally promotes AMPK-Drp1-dependent mitochondrial homeostasis in oligodendrocyte precursor cells, supporting their differentiation and myelination (PMID:40834529).

1. 2013 High

   Establishing PPP1R3G as a hepatic glycogen-targeting PP1 subunit resolved how this previously uncharacterized regulatory subunit participates in glucose and lipid metabolism — it dephosphorylates glycogen synthase via a glycogen-binding domain essential for both glycogen and triglyceride accumulation.

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

   PMID:24264575

   Open questions at the time

   • No structural information on PPP1R3G–PP1–glycogen synthase complex
   • Mechanism linking glycogen accumulation to triglyceride metabolism not resolved
2. 2016 High

   Extending PPP1R3G function to adipose tissue via whole-body knockout demonstrated that its glycogen-targeting role is not liver-restricted and established a genetic link between PPP1R3G-dependent glycogen metabolism and fat accumulation.

   Evidence Whole-body PPP1R3G knockout mice on high-fat diet, metabolic phenotyping, and 3T3-L1 adipocyte overexpression

   PMID:27815211

   Open questions at the time

   • Direct PP1 substrates in adipocytes beyond glycogen synthase not identified
   • Whether PPP1R3G affects insulin signaling directly in adipose tissue is unknown
3. 2021 High

   A genome-wide CRISPR screen revealed an entirely unexpected second function: PPP1R3G recruits PP1γ to TNFR1 complex I to dephosphorylate RIPK1 Ser25, converting PPP1R3G from a metabolic regulator to a critical enabler of TNF-driven apoptosis and necroptosis.

   Evidence CRISPR knockout screen, co-immunoprecipitation, PP1γ-binding mutant rescue, RIPK1 S25A mutant epistasis, and Ppp1r3g-knockout mice in TNF-SIRS model

   PMID:34862394

   Open questions at the time

   • How PPP1R3G is recruited to TNFR1 complex I is mechanistically undefined
   • Whether glycogen-binding and TNFR1-targeting functions are coordinately regulated is unknown
   • RIPK1 phosphorylation sites beyond Ser25 targeted by PPP1R3G–PP1γ not fully mapped
4. 2023 Medium

   PPP1R3G knockdown in trophoblasts implicated it upstream of Akt/MMP-9 signaling, suggesting a broader phosphatase-regulatory role beyond glycogen metabolism and RIPK1, though the direct mechanism is unresolved.

   Evidence Lentiviral knockdown in HTR-8/SVneo trophoblasts, western blotting for p-Akt, Transwell invasion and proliferation assays

   PMID:37642261

   Open questions at the time

   • No direct biochemical evidence that PPP1R3G–PP1 dephosphorylates Akt pathway components
   • Single cell line without in vivo validation
   • Mechanism connecting PPP1R3G to MMP-9 transcription not established
5. 2025 Medium

   Conditional deletion in oligodendrocyte precursor cells revealed that PPP1R3G maintains mitochondrial homeostasis via AMPK-Drp1 signaling, broadening its functional repertoire to include mitochondrial fission control and myelination.

   Evidence OPC-conditional Ppp1r3g knockout mice, primary OPC cultures, RNA-seq, TEM, mitochondrial functional assays, AMPK activation rescue

   PMID:40834529

   Open questions at the time

   • Direct PP1 substrate linking PPP1R3G to AMPK activation not identified
   • Whether the mitochondrial phenotype is cell-type specific or generalizable is unclear
   • Single-lab finding not yet independently replicated
6. 2026 High

   The RIPK1-activating function was extended to doxorubicin cardiotoxicity, where PPP1R3G removes p38-mediated inhibitory phosphorylation from RIPK1, establishing a feed-forward loop in which RIPK1 triggers mtDNA release, IFN-β signaling, ZBP1 induction, and amplified necroptosis.

   Evidence Ppp1r3g knockout mice treated with doxorubicin, cardiomyocyte assays, dissection of p38–RIPK1–mtDNA–IFN-β–ZBP1 signaling axis

   PMID:41984837

   Open questions at the time

   • Specific phospho-sites on RIPK1 removed by PPP1R3G–PP1 in the cardiac context beyond Ser25 not mapped
   • Whether PPP1R3G contributes to cardiotoxicity from other chemotherapeutics is untested

• It remains unknown how PPP1R3G is partitioned between its glycogen-targeting and TNFR1 complex I death-signaling functions, whether these are tissue-specific or signal-regulated, and what structural determinants dictate substrate selectivity of the PPP1R3G–PP1 holoenzyme.
• No structural model of PPP1R3G–PP1γ holoenzyme exists
• Signal-dependent regulation of PPP1R3G expression or post-translational modification is poorly characterized
• Whether the AMPK–Drp1 and Akt/MMP-9 functions reflect direct PP1 substrate dephosphorylation or indirect effects is unresolved