Affinage

CCPG1

Cell cycle progression protein 1 · UniProt Q9ULG6

Length
757 aa
Mass
87.3 kDa
Annotated
2026-06-09
13 papers in source corpus 8 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/6 claims corpus-supported (67%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCPG1 is an endoplasmic reticulum-resident transmembrane protein that serves as a non-canonical cargo receptor for selective autophagy of the ER (reticulophagy/ER-phagy), coupling ER proteostasis to the autophagosomal machinery (PMID:29290589, PMID:29916296, PMID:30263939). On its cytoplasmic face, CCPG1 directly engages ATG8-family proteins (LC3, GABARAP) through an LIR motif and independently binds FIP200/RB1CC1 through a discrete motif, with both interactions required for receptor function (PMID:29290589, PMID:29916296, PMID:30263939). Within the ER lumen, CCPG1 bears multiple conserved cargo-interacting regions (CIRs) that directly capture distinct aberrant or aggregation-prone luminal proteins—different CIRs binding the aggregation-prone 6xIAPP and the endogenous cargo P3H4—establishing CCPG1 as a bispecific receptor that bridges luminal cargo recognition to autophagic degradation (PMID:36735498, PMID:40395301). CCPG1 expression is induced downstream of ER stress via the unfolded protein response and the ATF4 axis, providing a feedback link from ER stress to ER-phagy (PMID:29290589, PMID:29916296, PMID:30263939, PMID:36769070); in vivo its loss causes ER luminal protein aggregation, UPR hyperactivation, and exocrine pancreas injury (PMID:29290589, PMID:29916296, PMID:30263939). Through this proteostatic surveillance, CCPG1 governs cell fate decisions in disease contexts, restraining aggregation of luminal proteins such as REG3B during KRAS-driven pancreatic pre-malignant transformation and supporting reticulophagy-dependent tumor growth in bladder cancer, where its LC3 interaction is functionally required (PMID:41361995). An earlier-characterized role as a scaffold that binds the RhoGEF Dbs to inhibit its RhoA-specific exchange activity and recruits Src into RhoGEF complexes (PMID:17000758) reflects a distinct, context-dependent function not yet integrated with its reticulophagy activity.

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2006 Medium

    Before any autophagy role was known, the question was what cellular activity CCPG1 carried; this established it as a scaffold that constrains the substrate specificity of a promiscuous RhoGEF.

    Evidence Co-IP, GEF activity assays, siRNA knockdown, and domain truncations in mammalian cells

    PMID:17000758

    Open questions at the time
    • Single lab; not reconciled with the later-defined ER-phagy function
    • No structural basis for selective inhibition of RhoA versus Cdc42 exchange
    • Functional significance of Src recruitment to Dbs complexes unresolved
  2. 2017 High

    The central question of CCPG1's physiological function was answered by defining it as a non-canonical ER-phagy cargo receptor that links ER stress to autophagic clearance and is required to protect tissue.

    Evidence Reciprocal Co-IP with LIR/FIP200-motif mutagenesis, UPR reporter assays, and an in vivo mouse knockout with histological and biochemical readouts

    PMID:29290589 PMID:29916296 PMID:30263939

    Open questions at the time
    • Did not identify the ER luminal cargoes captured by CCPG1
    • Structural basis of dual ATG8/FIP200 engagement not resolved
    • Mechanism coupling UPR transcriptional induction to receptor activity not detailed
  3. 2023 High

    How CCPG1 selects luminal cargo was unknown; mapping conserved cargo-interacting regions established it as a bispecific receptor that recognizes distinct luminal substrates directly.

    Evidence In vitro binding and pulldown assays with luminal-region truncation/deletion mutants plus cell-based degradation assays using 6xIAPP and P3H4

    PMID:36735498 PMID:40395301

    Open questions at the time
    • Full repertoire of endogenous luminal cargoes beyond P3H4 undefined
    • Structural determinants of CIR-cargo specificity not solved
  4. 2023 Medium

    The transcriptional wiring of CCPG1-mediated reticulophagy was clarified by placing it downstream of an ATF4–MAP1LC3A axis that governs cell death mode under ER stress.

    Evidence RNAi of ATF4 and CCPG1, ChIP-seq for ATF4 at the MAP1LC3A promoter, Co-IP of MAP1LC3A–CCPG1, and cell death assays in granulosa cells

    PMID:36769070

    Open questions at the time
    • Single lab and single cell type
    • Direct link between CCPG1 loss and the STAT1/STAT3-RIPK necroptosis switch is correlative
  5. 2025 Medium

    Whether CCPG1 reticulophagy is regulated and functionally consequential in cancer was tested, showing CCPG1 is suppressed via ATM–CHEK2 signaling and that its LC3 interaction drives pro-tumorigenic reticulophagy.

    Evidence Knockdown/overexpression of wild-type versus LC3-binding-deficient CCPG1, ATM-CHEK2 pathway inhibition, reticulophagy flux, and proliferation/apoptosis assays in bladder cancer cells

    PMID:41361995

    Open questions at the time
    • Single lab; in vivo tumor relevance not established
    • Direct biochemical link from CHEK2 to CCPG1 transcription not defined
  6. 2025 Medium

    The disease relevance of CCPG1 cargo recognition was extended by showing that failure to capture specific luminal proteins drives pre-malignant epithelial states.

    Evidence Proteomics, high-resolution imaging, spatial transcriptomics, CCPG1-deficient mice, and engineered REG3B interaction mutants (preprint)

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Causal contribution of CCPG1 loss versus REG3B aggregation alone needs separation
    • Generality across luminal cargoes in oncogenesis unknown
  7. 2025 Low

    The cargo range of CCPG1 was probed for ER-retained membrane proteins, implicating it in clearance of a pathogenic NMDAR variant.

    Evidence Pharmacological and genetic autophagy inhibition, LIR-motif disruption, and co-localization/interaction assays with CCPG1 and RTN3L (preprint)

    Open questions at the time
    • Single Co-IP/co-localization without reciprocal validation; preprint
    • CCPG1 role is a secondary finding in a GluN2B-focused study
    • Whether CCPG1 directly recognizes the variant or acts redundantly with RTN3L unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCPG1's RhoGEF-scaffolding activity relates mechanistically to its ER-phagy receptor function, and what governs its full endogenous cargo repertoire, remains unresolved.
  • No structural model of the dual cytoplasmic ATG8/FIP200 and luminal CIR architecture
  • No unified account reconciling the 2006 Dbs/Src scaffold role with reticulophagy
  • Comprehensive endogenous luminal cargo set undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
DBSGABARAPMAP1LC3AP3H4RB1CC1REG3BRTN3LSRC

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 CCPG1 is an ER-resident transmembrane protein that functions as a non-canonical autophagy cargo receptor for ER-phagy (reticulophagy). It directly binds to ATG8-family proteins (LC3, GABARAP) via an LIR motif, and independently and via a discrete motif binds to FIP200/RB1CC1. Both interactions are required for its function as a reticulophagy receptor. CCPG1 transcription is induced by the unfolded protein response, directly linking ER stress to ER-phagy. In vivo, CCPG1 loss causes ER luminal protein aggregation, UPR hyperactivation, and exocrine pancreas tissue injury. Co-immunoprecipitation, motif mutagenesis, in vivo mouse knockout with histological and biochemical readouts, UPR reporter assays Developmental Cell High 29290589 29916296 30263939
2006 CCPG1 (originally identified as a scaffold protein) binds to the DH/PH domain tandem of the RhoGEF Dbs and inhibits Dbs exchange activity toward RhoA but not Cdc42, thereby restricting substrate utilization of this promiscuous RhoGEF. The isolated Dbs-binding domain of CCPG1 was not sufficient to suppress RhoA exchange activity, indicating a regulatory (not merely tethering) interaction. CCPG1 also recruits endogenous Src kinase into Dbs-containing complexes and interacts with Cdc42. Co-immunoprecipitation, GEF activity assays in mammalian cells, siRNA knockdown of endogenous CCPG1, domain truncation experiments Molecular and Cellular Biology Medium 17000758
2023 The ER luminal region of CCPG1 contains several highly conserved cargo-interacting regions (CIRs) that directly interact with specific ER luminal cargo proteins for ER-phagy. The aggregation-prone 6xIAPP and the endogenous cargo P3H4 bind to different CIRs, establishing CCPG1 as a bispecific ER-phagy receptor that bridges ER luminal cargo recognition with the autophagosomal membrane machinery. In vitro binding assays, pulldown experiments with truncation/deletion mutants of CCPG1 luminal region, cell-based degradation assays with 6xIAPP and P3H4 as substrates Molecular Biology of the Cell High 36735498 40395301
2023 In granulosa cells, ER stress activates reticulophagy through an ATF4–MAP1LC3A–CCPG1 pathway. ATF4 transcriptionally targets MAP1LC3A, and MAP1LC3A physically interacts with CCPG1 (demonstrated by Co-IP). CCPG1 knockdown shifts granulosa cell death from apoptosis to necroptosis mediated via STAT1/STAT3-(p)RIPK1-(p)RIPK3-(p)MLKL, impairing ER proteostasis. RNAi knockdown of ATF4 and CCPG1, ChIP-seq (ATF4 at MAP1LC3A promoter), co-immunoprecipitation (MAP1LC3A–CCPG1 interaction), cell death assays International Journal of Molecular Sciences Medium 36769070
2025 Cisplatin treatment inhibits reticulophagy by downregulating CCPG1 expression through the ATM–CHEK2/Chk2 signaling pathway in bladder cancer cells. Overexpression of wild-type CCPG1, but not an LC3-binding-deficient variant, rescues reticulophagy and promotes tumor growth, establishing that the LC3-interaction of CCPG1 is functionally required for its pro-tumorigenic reticulophagy activity. CCPG1 knockdown and overexpression (wild-type vs. LC3-binding-deficient mutant), pharmacological inhibition of ATM-CHEK2 pathway, reticulophagy flux assays, cell proliferation and apoptosis assays Autophagy Medium 41361995
2025 In KRAS-driven pancreatic oncogenesis, ER-phagy failure causes pathologic aggregation of a subset of ER luminal proteins, including REG3B, due to failure to physically interact with the ER-phagy receptor CCPG1. Engineered REG3B mutants that cannot bind CCPG1 and form aggregates are sufficient to drive acinar-ductal metaplasia-primed epithelial cell states, placing CCPG1 upstream of proteostatic control of pre-malignant transformation. Proteomics, high-resolution imaging, spatial transcriptomics, genetically engineered CCPG1-deficient mice, REG3B interaction mutants bioRxiv (preprint)preprint Medium
2025 The pathogenic R519Q GluN2B NMDAR variant retained in the ER is recognized by the ER-phagy receptor CCPG1 (along with RTN3L) for autophagic clearance via the lysosomal pathway. Pharmacological and genetic autophagy inhibition, LIR-motif disruption of GluN2B, co-localization and interaction assays with CCPG1 and RTN3L bioRxiv (preprint)preprint Low

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis. Developmental cell 372 29290589
2017 miR-498 promotes cell proliferation and inhibits cell apoptosis in retinoblastoma by directly targeting CCPG1. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 27 29247256
2023 The Activation of Reticulophagy by ER Stress through the ATF4-MAP1LC3A-CCPG1 Pathway in Ovarian Granulosa Cells Is Linked to Apoptosis and Necroptosis. International journal of molecular sciences 22 36769070
2018 CCPG1, a cargo receptor required for reticulophagy and endoplasmic reticulum proteostasis. Autophagy 21 29916296
2023 CCPG1 recognizes endoplasmic reticulum luminal proteins for selective ER-phagy. Molecular biology of the cell 20 36735498
2006 Ccpg1, a novel scaffold protein that regulates the activity of the Rho guanine nucleotide exchange factor Dbs. Molecular and cellular biology 17 17000758
2022 Piperine alleviates acute pancreatitis: A possible role for FAM134B and CCPG1 dependent ER-phagy. Phytomedicine : international journal of phytotherapy and phytopharmacology 14 35963197
2018 CCPG1 is a noncanonical autophagy cargo receptor essential for reticulophagy and pancreatic ER proteostasis. Autophagy 14 29911925
2018 CCPG1, an unconventional cargo receptor for ER-phagy, maintains pancreatic acinar cell health. Molecular & cellular oncology 14 30263939
2023 Sodium arsenite-induced cytotoxicity is regulated by BNIP3L/Nix-mediated endoplasmic reticulum stress responses and CCPG1-mediated endoplasmic reticulum-phagy. Environmental toxicology and pharmacology 3 36925093
2022 CCPG1 involved in corneal Aspergillus fumigatus infection. International journal of ophthalmology 2 35450172
2025 CCPG1-mediated reticulophagy promotes tumorigenesis and cisplatin resistance in bladder cancer. Autophagy 1 41361995
2023 Cargo-interacting regions (CIR) of CCPG1 capture ER luminal cargos for reticulophagy. Autophagy reports 0 40395301

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