Affinage

GOLIM4

Golgi integral membrane protein 4 · UniProt O00461

Length
696 aa
Mass
81.9 kDa
Annotated
2026-04-28
15 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GOLIM4 (GPP130) is a type II cis-Golgi membrane protein that functions as a pH-sensitive trafficking receptor cycling between the Golgi and endosomes, and as a manganese sensor that couples changes in lumenal metal ion concentration to regulated protein degradation. Its lumenal stem domain directly binds the Shiga toxin (STx/STx1) B subunit through a seven-residue stretch and is required for retrograde endosome-to-Golgi transport of the toxin; the same stem domain senses sub-micromolar manganese, triggering GPP130 oligomerization, recognition by the sorting receptor sortilin, and Rab7-dependent delivery to lysosomes (PMID:23761068, PMID:20130081, PMID:28768823). GOLIM4 also regulates post-Golgi trafficking of surface proteins including Talin 1, MHC class I molecules, and multiple growth factor receptors and adhesion molecules, thereby influencing cell motility, adhesion, and proliferation (PMID:40632561, PMID:40649939). Its expression is transcriptionally regulated by the IRE1α/XBP1s ER-stress axis, and it can be proteolytically shed by PC7/Furin to generate secreted fragments that enhance cell proliferation (PMID:40649939).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1997 High

    Establishing GOLIM4 as a cis-Golgi resident with a saturable, pH-dependent retrieval mechanism resolved how an integral membrane protein cycles through endocytic compartments yet maintains steady-state Golgi localization.

    Evidence cDNA cloning, overexpression-induced endosome accumulation, chloroquine redistribution assays with immunofluorescence and EM in cultured cells

    PMID:9201717

    Open questions at the time
    • molecular determinants of the retrieval signal unknown
    • identity of retrieval receptor or coat machinery not determined
  2. 2007 Medium

    Quantitative dissection of GPP130 cycling kinetics revealed that its trafficking includes intra-Golgi, trans-Golgi-to-endosome, and endosome-to-Golgi steps, with pH perturbation (monensin) primarily affecting the trans-Golgi stage, clarifying where pH sensitivity operates.

    Evidence quantitative fluorescence microscopy with Shiga-like toxin B and tsO45-GFP probes, kinetic modeling

    PMID:17605763

    Open questions at the time
    • molecular basis of pH sensitivity in the lumenal domain not identified
    • trans-Golgi sorting machinery not determined
  3. 2010 High

    Identification of the GPP130 lumenal stem domain as a manganese sensor that is necessary and sufficient for Mn-induced redistribution to multivesicular bodies and lysosomal degradation via Rab7 revealed a novel mechanism linking metal ion exposure to selective Golgi protein turnover.

    Evidence domain deletion/swap chimeras, Rab7 dominant-negative, live-cell imaging, pulse-chase degradation in cultured cells

    PMID:20130081

    Open questions at the time
    • structural mechanism of Mn binding/sensing in the stem domain unknown
    • how Rab7-dependent pathway is engaged not determined
  4. 2013 High

    Demonstration that GPP130 directly binds STx/STx1 B subunit through a defined seven-residue stretch and is required for retrograde endosome-to-Golgi trafficking of these toxins established GPP130 as a bona fide cargo receptor, while explaining the selective inability of Mn-induced GPP130 depletion to block STx2.

    Evidence pulldowns with purified toxin B subunits, site-directed mutagenesis, cell-based toxin trafficking assays

    PMID:23761068

    Open questions at the time
    • crystal structure of GPP130–STx B complex not available
    • whether additional endogenous cargoes use this binding site unknown
  5. 2013 Medium

    The metal specificity screen showed GPP130 degradation is exquisitely selective for Mn among transition metals and occurs at sub-micromolar concentrations in neuronal cells and in vivo in rat brain, establishing GPP130 as a physiologically relevant Mn indicator.

    Evidence metal panel (Co, Cu, Fe, Ni, Zn vs Mn) in AF5 cells, in vivo subchronic Mn exposure in rats

    PMID:23280773

    Open questions at the time
    • direct Mn binding stoichiometry and affinity not measured
    • whether GPP130 degradation has a protective function in Mn homeostasis unclear
  6. 2017 High

    Identification of sortilin as the sorting receptor that recognizes Mn-induced GPP130 oligomers in the Golgi and directs them to lysosomes resolved the missing link between Mn sensing and degradative sorting.

    Evidence sortilin knockdown, Co-IP with domain deletions, FM-domain aggregation control, immunofluorescence

    PMID:28768823

    Open questions at the time
    • structural basis for sortilin recognition of GPP130 oligomers unknown
    • whether oligomerization is directly triggered by Mn binding or indirectly by pH change not resolved
  7. 2021 Medium

    Discovery that RBFOX2-regulated alternative splicing of GOLIM4 exon-7 generates a long isoform (GOLIM4-L) important for Golgi integrity, and that GOLIM4 interacts with RAB26 to influence vesicle-mediated transport, expanded the functional repertoire beyond Mn sensing and toxin trafficking.

    Evidence splicing profiling, RBFOX2 knockdown/overexpression, Co-IP of GOLIM4–RAB26, luciferase splicing reporter in NPC cells

    PMID:34180133

    Open questions at the time
    • functional difference between GOLIM4-L and short isoform not fully characterized
    • GOLIM4–RAB26 interaction not validated by reciprocal pull-down or structural methods
  8. 2025 Medium

    Establishing that proprotein convertases PC7 and Furin cleave GPP130 to generate secreted C-terminal fragments that enhance cell proliferation revealed a non-canonical signaling output of a Golgi trafficking receptor.

    Evidence cell-based cleavage assays with PC7/Furin overexpression and knockdown, proliferation assays in A549, SKOV3, HeLa cells

    PMID:40649939

    Open questions at the time
    • identity of the receptor or pathway through which shed fragments promote proliferation unknown
    • cleavage sites not mapped at residue level
    • in vivo relevance not tested
  9. 2025 Medium

    Demonstration that GOLIM4 regulates post-Golgi trafficking of Talin 1 and thereby controls cell motility and adhesion, with both genes co-regulated by miR-200b during EMT, placed GOLIM4 in an epithelial-mesenchymal transition circuit beyond its canonical Golgi cycling role.

    Evidence monensin-induced exocytosis, GOLIM4/TLN1 knockdown, migration assays, miR-200b target validation, Golgi pH measurement

    PMID:40632561

    Open questions at the time
    • mechanism by which GOLIM4 sorts TLN1 cargo not determined
    • direct GOLIM4–TLN1 interaction not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis for manganese sensing in the lumenal stem domain, whether GOLIM4 has additional endogenous retrograde trafficking cargoes beyond Shiga toxin, and the physiological significance of PC7/Furin-generated GOLIM4 fragments in vivo.
  • no atomic-resolution structure of GOLIM4 lumenal domain or its Mn-bound state
  • endogenous cargoes for the retrograde trafficking receptor function remain unidentified
  • in vivo role of shed GOLIM4 fragments untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140299 molecular sensor activity 2 GO:0038024 cargo receptor activity 1
Localization
GO:0005794 Golgi apparatus 3 GO:0005764 lysosome 2 GO:0005768 endosome 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-392499 Metabolism of proteins 2 R-HSA-9609507 Protein localization 2
Partners
FURINPCSK7RAB26RAB7ARBFOX2SORT1TLN1

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 GPP130 (GOLIM4) is a type II integral membrane protein localized to the cis/medial Golgi with an unusually acidic lumenal domain and multiple coiled-coil regions. Overexpression causes accumulation in endocytic vesicles, and chloroquine treatment reversibly redistributes endogenous GPP130 to endocytic vesicles, demonstrating that its Golgi targeting is saturable and pH-sensitive, involving a retrieval mechanism for return to the Golgi. cDNA sequencing, overexpression, chloroquine treatment with immunofluorescence and electron microscopy, subcellular fractionation Molecular biology of the cell High 9201717
2007 GPP130 cycling is regulated at multiple stages: intra-Golgi cycling, trans-Golgi to endosome transport, and endosome-to-Golgi transport. pH perturbation (monensin) most strongly affects the trans-Golgi, the most acidic portion of the Golgi apparatus. Quantitative fluorescence microscopy with Shiga-like toxin B fragment as trafficking probe, tsO45-GFP as secretory marker, simulations of trafficking kinetics Traffic (Copenhagen, Denmark) Medium 17605763
2010 Extracellular manganese (Mn) induces rapid redistribution of GPP130 from the cis-Golgi to multivesicular bodies via a Rab7-dependent pathway, followed by lysosomal degradation. The lumenal stem domain of GPP130 acts as a Mn sensor and is required and sufficient to confer Mn sensitivity to another cis-Golgi protein. The cytoplasmic domain is dispensable. GPP130 must be targeted to the cis-Golgi for the Mn response to occur. Immunofluorescence, domain deletion/swap experiments, Rab7 dominant-negative inhibition, live-cell imaging, pulse-chase degradation assays Molecular biology of the cell High 20130081
2013 GPP130 directly binds the B subunit of Shiga toxin (STx) and STx1 via a seven-residue stretch in its lumenal stem domain adjacent to the transmembrane domain. This interaction is required for retrograde endosome-to-Golgi trafficking of STx/STx1. STx2 B subunit does not bind GPP130, explaining why Mn-induced GPP130 down-regulation fails to block STx2 trafficking. Pulldown with purified toxin B subunits, mutagenesis of GPP130 stem domain and toxin residues, cell-based Shiga toxin trafficking assays Molecular biology of the cell High 23761068
2013 GPP130 degradation in response to Mn is specific to Mn among transition metals tested (cobalt, copper, iron, nickel, zinc did not induce degradation) and occurs at sub-micromolar extracellular Mn concentrations without detectable increases in intracellular Mn, demonstrating exquisite selectivity of the GPP130 Mn-sensing mechanism in neuronal cells and in vivo in rat brain. Immunofluorescence quantification in AF5 cells, western blot, in vivo rat subchronic Mn exposure model Synapse (New York, N.Y.) Medium 23280773
2017 Mn-induced exit of GPP130 from the trans-Golgi network toward lysosomes is mediated by the sorting receptor sortilin, which interacts with the lumenal stem domain of GPP130. Mn causes GPP130 to oligomerize/aggregate in the Golgi, and sortilin sorts these complexes for lysosomal delivery. In contrast, FM-domain-induced lysosomal trafficking of galactosyltransferase was sortilin-independent. Sortilin knockdown, Co-IP/interaction assays, domain deletion experiments, self-interacting FM domain aggregation system, immunofluorescence Molecular biology of the cell High 28768823
2021 RBFOX2 binds a GGAA motif in exon-7 of GOLIM4 pre-mRNA and promotes inclusion of exon-7, generating the long isoform GOLIM4-L. GOLIM4-L and RBFOX2 maintain Golgi apparatus organization and influence vesicle-mediated transport. RAB26 interacts with GOLIM4 and mediates its tumorigenic effects in NPC cells. Transcriptome splicing profiling, RBFOX2 knockdown/overexpression rescue experiments, Co-IP (GOLIM4-RAB26 interaction), luciferase splicing reporter, immunofluorescence of Golgi organization Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 34180133
2025 GPP130 is a substrate of proprotein convertases PC7 (PCSK7) and Furin, which cleave/shed GPP130 into a membrane-bound N-terminal product and secreted C-terminal fragments. GPP130 overexpression increases cell proliferation in A549, SKOV3, and HeLa cells, and this proliferative activity is enhanced upon cleavage by PC7 and/or Furin. Cell-based cleavage assays, overexpression and knockdown, proliferation assays, western blot for cleavage products International journal of molecular sciences Medium 40649939
2025 Monensin increases Golgi lumenal pH, inducing rapid exocytosis of GOLIM4 from the Golgi. GOLIM4 regulates cell motility and adhesion by modulating post-Golgi trafficking of Talin 1 (TLN1), an essential focal adhesion component. Both GOLIM4 and TLN1 are direct targets of microRNA-200b, which is suppressed during EMT. Monensin treatment with live-cell imaging, GOLIM4 and TLN1 knockdown, migration assays, microRNA-200b target validation, Golgi pH measurement Proceedings of the National Academy of Sciences of the United States of America Medium 40632561
2024 IRE1α regulates GOLIM4 expression via the XBP1s transcription factor downstream of ER stress. GOLIM4 silencing reduces surface expression of MHC class I molecules, growth factor receptors (PDGFRA, IL13RA2), and adhesion/migration proteins (CD44, CD54, NCAM1, ITGB1, CD90) without affecting their mRNA levels, demonstrating that GOLIM4 controls post-transcriptional surface trafficking of these molecules. GOLIM4 silencing impairs glioblastoma cell-cell adhesion and migration. IRE1 inhibition, XBP1s overexpression, GOLIM4 siRNA knockdown, flow cytometry for surface protein expression, qRT-PCR to exclude transcriptional effects, cell adhesion and migration assays bioRxivpreprint Medium bio_10.1101_2024.10.22.619629
2021 miR-105-3p directly targets the GOLIM4 3'UTR (validated by luciferase reporter assay) and suppresses GOLIM4 expression, promoting breast cancer cell proliferation and metastasis. Luciferase reporter assay, GOLIM4 silencing rescue experiment, CCK-8, Transwell, TUNEL assays BMC cancer Low 33722196

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Sequence and overexpression of GPP130/GIMPc: evidence for saturable pH-sensitive targeting of a type II early Golgi membrane protein. Molecular biology of the cell 104 9201717
2010 Manganese-induced trafficking and turnover of the cis-Golgi glycoprotein GPP130. Molecular biology of the cell 64 20130081
2013 Shiga toxin-binding site for host cell receptor GPP130 reveals unexpected divergence in toxin-trafficking mechanisms. Molecular biology of the cell 33 23761068
2001 Antibody responses to recombinant Epstein-Barr virus antigens in nasopharyngeal carcinoma patients: complementary test of ZEBRA protein and early antigens p54 and p138. Journal of clinical microbiology 31 11526145
2021 RBFOX2/GOLIM4 Splicing Axis Activates Vesicular Transport Pathway to Promote Nasopharyngeal Carcinogenesis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 25 34180133
2021 MiR-105-3p acts as an oncogene to promote the proliferation and metastasis of breast cancer cells by targeting GOLIM4. BMC cancer 21 33722196
2007 Both post-Golgi and intra-Golgi cycling affect the distribution of the Golgi phosphoprotein GPP130. Traffic (Copenhagen, Denmark) 17 17605763
2013 Golgi phosphoprotein 4 (GPP130) is a sensitive and selective cellular target of manganese exposure. Synapse (New York, N.Y.) 15 23280773
2017 Manganese-induced trafficking and turnover of GPP130 is mediated by sortilin. Molecular biology of the cell 13 28768823
1995 Golgi membrane vesicles in HeLa mitotic cells are identified with monoclonal antibody made against Golgi cisternal membrane protein p138. Cell structure and function 6 8825065
2025 Small extracellular vesicles from human umbilical cord mesenchymal stem cells delivering miR-202-5p alleviate renal ischemia-reperfusion injury by targeting the GOLIM4/PI3K/AKT axis. Frontiers in immunology 3 40519909
2002 Expression of Golgi membrane protein p138 is cell cycle-independent and dissociated from centrosome duplication. Cell structure and function 3 12207053
2022 CircRNA RNF10 inhibits tumorigenicity by targeting miR-942-5p/GOLIM4 axis in breast cancer. Environmental and molecular mutagenesis 2 36054164
2025 Shedding of GPP130 by PC7 and Furin: Potential Implication in Lung Cancer Progression. International journal of molecular sciences 1 40649939
2025 Monensin suppresses EMT-driven cancer cell motility by inducing Golgi pH-dependent exocytosis of GOLIM4. Proceedings of the National Academy of Sciences of the United States of America 0 40632561