Affinage

YIPF5

Protein YIPF5 · UniProt Q969M3

Length
257 aa
Mass
28.0 kDa
Annotated
2026-06-11
18 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

YIPF5 is a multi-spanning ER/ER-Golgi intermediate compartment membrane protein that organizes the early secretory pathway, coupling ER membrane architecture to COPII-dependent anterograde export and bidirectional ER-Golgi trafficking (PMID:19509059, PMID:20237155). It is required to maintain a dispersed ER network: its depletion restructures the ER into concentric whorls and slows COPII-mediated cargo export, a function that maps to discrete determinants in its cytoplasmic (E95/L92/L96) and transmembrane (K146/V152) domains that are distinct from the binding sites for its partner Yif1 and Rab GTPases (PMID:20237155, PMID:23342155, PMID:15990086). On the trafficking side, YIPF5 mediates COPI-independent retrograde Golgi-to-ER transport via Rab6 membrane recruitment (PMID:19509059), and directly binds the ER export receptor SURF4 to negatively regulate SURF4-dependent ER export of a subset of cargoes including neuronal adhesion molecules (PMID:41717013). YIPF5 also activates the IRE1 (and PERK) branches of the unfolded protein response by promoting high-order IRE1 assembly at ER exit sites, a stress-response output that promotes survival in cancer cells (PMID:25742138, PMID:28358375). Through these activities YIPF5 supports specific cargo trafficking and innate immune signaling: it facilitates STING recruitment to COPII vesicles and ER-to-Golgi transit during cytoplasmic DNA sensing (PMID:31391232), and is required for ER-to-Golgi trafficking of proinsulin in β cells, where its loss causes proinsulin retention, ER stress, and β cell failure (PMID:33164986). Loss-of-function and disease-associated mutations link YIPF5 to β cell failure and to primary microcephaly with impaired cortical progenitor generation and premature neuronal migration (PMID:33164986, PMID:37142085, PMID:41717013).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 Medium

    Establishing YIPF5's first physical partner addressed whether it functions through a defined binding interaction, showing it determines Golgi localization of Yif1.

    Evidence Yeast two-hybrid, Co-IP, and dominant-negative cytoplasmic-domain mutant in human cells

    PMID:15990086

    Open questions at the time
    • Functional consequence of the YIPF5–Yif1 complex for trafficking not defined
    • No structural detail of the interaction
  2. 2009 Medium

    Defined YIPF5's directionality in the secretory pathway by showing it acts in COPI-independent retrograde Golgi-to-ER transport rather than anterograde flux.

    Evidence RNAi knockdown, recombinant N-terminal domain inhibition, Shiga toxin/VSVG transport assays, and Rab6 membrane fractionation

    PMID:19509059

    Open questions at the time
    • Mechanism of Rab6 membrane recruitment by YIPF5 not resolved
    • Direct cargo selectivity for retrograde route not mapped
  3. 2010 High

    Connected YIPF5 to ER membrane architecture by showing it prevents ER whorl formation and supports COPII export, localizing the function to a single conserved residue.

    Evidence RNAi depletion, live-cell/EM ER morphology, COPII export assays, and E95K site-directed mutagenesis

    PMID:20237155

    Open questions at the time
    • Molecular partner mediating ER dispersal not identified
    • Link between whorl prevention and export rate left mechanistically implicit
  4. 2013 Medium

    Refined the structure-function map by separating ER-organization determinants from known partner-binding sites, implying a novel unidentified effector.

    Evidence Comprehensive mutagenesis with ER morphology readouts and Yif1A knockdown controls

    PMID:23342155

    Open questions at the time
    • The hypothesized novel binding partner was never identified
    • Whether transmembrane (K146/V152) and cytoplasmic (E95) determinants act in the same pathway is unresolved
  5. 2015 Medium

    Identified YIPF5 as an activator of the UPR by showing it drives high-order IRE1 assembly at ER exit sites, linking secretory-pathway architecture to stress signaling.

    Evidence RNAi knockdown, IRE1 phosphorylation assays, ERES microscopy, and Brucella vacuole-formation infection model

    PMID:25742138

    Open questions at the time
    • Whether YIPF5 directly contacts IRE1 versus scaffolds ERES is unclear
    • Physiological trigger that engages this function not defined
  6. 2017 Medium

    Extended UPR control to constitutive activation of both IRE1 and PERK that sustains cancer cell survival, framing YIPF5 as a pro-survival node.

    Evidence RNAi knockdown with IRE1/PERK pathway readouts and apoptosis assays in cervical cancer cells

    PMID:28358375

    Open questions at the time
    • Mechanism of PERK arm engagement distinct from IRE1 not dissected
    • Generality beyond cervical cancer lines untested
  7. 2019 Medium

    Placed YIPF5 in innate immunity by showing it bridges STING to COPII vesicles to drive STING ER-to-Golgi trafficking and type I IFN.

    Evidence Co-IP of YIPF5 with STING and COPII components, RNAi knockdown, and IFN/viral infection assays

    PMID:31391232

    Open questions at the time
    • Whether STING is a direct cargo of YIPF5-assisted COPII selection is not established
    • Reciprocal interaction validation limited
  8. 2020 High

    Demonstrated cargo-specific physiological importance by showing YIPF5 is essential for proinsulin ER-to-Golgi trafficking, with loss causing β cell ER stress and failure.

    Evidence RNAi silencing, KO/knockin embryonic stem cells, and patient-derived iPSC islet cells with proinsulin localization and ER stress/apoptosis readouts

    PMID:33164986

    Open questions at the time
    • Whether proinsulin export depends on the SURF4 or COPII activities of YIPF5 not resolved here
    • Mechanism linking trafficking defect to UPR amplitude not fully dissected
  9. 2023 Medium

    Linked a specific YIPF5 mutation to neurodevelopment by showing p.W218R induces neuronal ER stress and impairs apical progenitor generation, causing microcephaly.

    Evidence Base-edited knockin rabbit model with cortical progenitor analysis and ER stress markers

    PMID:37142085

    Open questions at the time
    • How the mutation alters specific YIPF5 trafficking functions is not defined
    • Cell-type-specific cargo defects in neurons not identified
  10. 2026 High

    Identified SURF4 as a direct partner and revealed YIPF5 as a negative regulator of SURF4-mediated ER export, connecting it to neuronal surface composition and migration in vivo.

    Evidence Co-IP, KO cell surface proteomics/secretome, ERGIC53/Rab1 tubule imaging, kinetic export assays, and in utero mouse brain knockdown

    PMID:41717013

    Open questions at the time
    • Structural basis of YIPF5–SURF4 antagonism not solved
    • Full cargo repertoire under YIPF5/SURF4 control incomplete
  11. 2025 Medium

    Showed YIPF5 is hijacked by coronaviruses, interacting with nsp3/nsp4/nsp6 to support double-membrane vesicle biogenesis required for replication.

    Evidence Genome-wide CRISPR screen, KO, Co-IP with viral nsps, and DMV electron microscopy with replication assays

    PMID:40422075

    Open questions at the time
    • Whether DMV support reflects normal ER-membrane organizing activity is unclear
    • Direct versus indirect nsp interactions not distinguished
  12. 2026 Medium

    Characterized post-transcriptional control of YIPF5 levels via rare-codon-coupled mRNA decay and 3' UTR elements, addressing how its abundance is tuned.

    Evidence Codon usage analysis, 3' UTR deletion mapping, and mRNA/protein reporter quantification

    PMID:41940818

    Open questions at the time
    • Translation-coupled decay pathway not orthogonally validated
    • Physiological conditions regulating these elements unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the effector mediating YIPF5-dependent ER membrane dispersal, and how its trafficking, ER-organization, and UPR-activating functions are mechanistically integrated, remain unresolved.
  • Novel ER-organization binding partner unidentified
  • No structural model of YIPF5 or its complexes
  • Whether retrograde, anterograde-regulatory, and UPR roles share one biochemical mechanism is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005794 Golgi apparatus 3
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9609507 Protein localization 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-168256 Immune System 1
Partners
IRE1RAB6STING1SURF4YIF1A

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Yip1A (YIPF5) localizes to the ER-Golgi intermediate compartment (ERGIC) and regulates COPI-independent retrograde transport from the Golgi to the ER. Knockdown delayed Shiga toxin transport from Golgi to ER but did not affect anterograde VSVGts045 transport. The N-terminal cytoplasmic domain of Yip1A inhibited COPI-independent retrograde transport of GT-GFP. Yip1A knockdown also caused dissociation of Rab6 from membranes. RNAi knockdown, recombinant N-terminal domain inhibition assay, intracellular transport assays, immunofluorescence, membrane fractionation Journal of cell science Medium 19509059
2010 Yip1A (YIPF5) is required for ER network dispersal; depletion causes restructuring of the ER into concentric whorls and markedly slows COPII-mediated protein export. A single conserved amino acid substitution (E95K) in the N-terminal cytoplasmic domain blocks the ER network dispersal function of Yip1A. RNAi depletion, live-cell and electron microscopy of ER morphology, COPII cargo export assays, site-directed mutagenesis (E95K) Molecular biology of the cell High 20237155
2013 Mutational analysis of Yip1A identified two discrete functionally required determinants for ER whorl regulation: residues E95/L92/L96 in the cytoplasmic domain, and K146/V152 in the transmembrane domain. These sites are distinct from the binding sites for established partners Yif1A and Ypt1/Ypt31 Rab GTPases, suggesting Yip1A controls ER membrane organization through a novel binding partner. Yif1A knockdown did not cause ER whorl formation, supporting uncoupling of partner binding from ER organization. Comprehensive mutagenesis of Yip1A, ER morphology assays, Yif1A knockdown, functional complementation PloS one Medium 23342155
2005 Human Yip1A (YIPF5) interacts with human Yif1 (HsYif1) and specifies its localization to the Golgi apparatus. Overexpression of a cytoplasmic domain-deleted mutant of HsYip1A disrupts the Golgi localization of HsYif1. Yeast two-hybrid, immunoprecipitation pulldown, immunofluorescence co-localization, dominant-negative mutant overexpression Biochemical and biophysical research communications Medium 15990086
2015 Yip1A (YIPF5) is a host factor required for activation of the IRE1 pathway of the unfolded protein response (UPR). Yip1A mediates IRE1 phosphorylation through high-order assembly of IRE1 molecules at ER exit sites (ERES) under UPR conditions. In Yip1A-knockdown cells, Brucella abortus failed to generate ER-derived vacuoles and remained in endosomal/lysosomal compartments. RNAi knockdown, IRE1 phosphorylation assays, fluorescence and electron microscopy of ER exit sites and vacuole formation, infection experiments PLoS pathogens Medium 25742138
2017 Yip1A (YIPF5) constitutively activates both the IRE1 and PERK pathways of the UPR in HeLa and CaSki cervical cancer cells, mediating IRE1 phosphorylation and PERK transcription, thereby upregulating anti-apoptotic proteins and autophagy-related proteins to promote cancer cell survival. Depletion of Yip1A by RNAi induced apoptotic cell death. RNAi knockdown, UPR pathway assays (IRE1 phosphorylation, PERK transcription), apoptosis assays, western blotting Cell death & disease Medium 28358375
2019 YIPF5 positively regulates STING-mediated innate immune responses by interacting with both STING and COPII components, facilitating STING recruitment to COPII vesicles and promoting STING trafficking from the ER to the Golgi upon cytoplasmic dsDNA stimulation. Knockdown of YIPF5 impairs type I IFN production in response to DNA viruses. Co-immunoprecipitation (YIPF5 with STING and COPII components), RNAi knockdown, type I IFN production assays, viral infection assays Journal of immunology Medium 31391232
2020 Loss of YIPF5 function in stem cell-derived islet cells causes proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing increases β cell sensitivity to ER stress-induced apoptosis. This establishes YIPF5 as essential for ER-to-Golgi trafficking of proinsulin in β cells. RNAi silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, patient-derived iPSCs differentiated to islet cells, proinsulin localization by immunofluorescence, ER stress markers, apoptosis assays The Journal of clinical investigation High 33164986
2023 The YIPF5 (p.W218R) mutation causes ER stress in cortical neurons and interferes with generation of apical progenitors (APs) in the developing cortex, leading to primary microcephaly. The mutant rabbit model links YIPF5 loss-of-function to unfolded protein response induction and neurodevelopmental defects. SpRY-ABEmax base editing to generate knockin rabbits, cortical progenitor analysis, ER stress markers, behavioral and morphological phenotyping Neurobiology of disease Medium 37142085
2025 YIPF5 interacts with viral non-structural proteins nsp3, nsp4, and nsp6 and facilitates formation of double-membrane vesicles (DMVs) during PEDV coronavirus infection. YIPF5 knockout suppresses PEDV replication and disrupts the nsp3–nsp4 interaction required for DMV biogenesis. Whole-genome CRISPR/Cas9 screens, YIPF5 knockout, Co-immunoprecipitation with viral nsps, DMV morphology by electron microscopy, viral replication assays Journal of virology Medium 40422075
2026 YIPF5 directly interacts with the ER export receptor SURF4 and negatively regulates SURF4-mediated ER export of a subset of proteins including neuronal adhesion molecules. YIPF5 knockout causes elongated ERGIC53- and Rab1-positive tubules from ER exit sites, alters SURF4 localization, and shifts the cell surface and secretome composition. In utero knockdown of Yipf5 in embryonic mouse brains induces premature neuronal migration and abnormal neuronal morphology. Co-immunoprecipitation (YIPF5–SURF4 interaction), YIPF5 knockout cells, cell surface proteomics and secretome analysis, live-cell imaging of ERGIC53/Rab1 tubules, kinetic ER export assays, in utero knockdown in mouse embryonic brain iScience High 41717013
2026 YIPFα1A (YIPF5) expression is post-transcriptionally regulated by rare-codon enrichment in the CDS (suppressing expression at the mRNA level via translation-coupled mRNA decay) and by the 3' UTR: a proximal segment (51-150) stabilizes mRNA increasing both mRNA and protein levels, while a distal segment (1116-2230) increases mRNA but reduces translation efficiency. Codon usage analysis, 3' UTR deletion mapping, mRNA and protein quantification, reporter assays FEBS open bio Medium 41940818

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress. The Journal of clinical investigation 74 33164986
2015 Yip1A, a novel host factor for the activation of the IRE1 pathway of the unfolded protein response during Brucella infection. PLoS pathogens 63 25742138
2019 YIPF5 Is Essential for Innate Immunity to DNA Virus and Facilitates COPII-Dependent STING Trafficking. Journal of immunology (Baltimore, Md. : 1950) 54 31391232
2009 Yip1A regulates the COPI-independent retrograde transport from the Golgi complex to the ER. Journal of cell science 39 19509059
2010 Yip1A structures the mammalian endoplasmic reticulum. Molecular biology of the cell 34 20237155
2005 Cloning, cellular localization, genomic organization, and tissue-specific expression of the TGFbeta1-inducible SMAP-5 gene. Gene 28 15922870
2017 Novel prosurvival function of Yip1A in human cervical cancer cells: constitutive activation of the IRE1 and PERK pathways of the unfolded protein response. Cell death & disease 21 28358375
2005 Human Yip1A specifies the localization of Yif1 to the Golgi apparatus. Biochemical and biophysical research communications 19 15990086
2023 Vitamin D receptor (VDR) mediates the quiescence of activated hepatic stellate cells (aHSCs) by regulating M2 macrophage exosomal smooth muscle cell-associated protein 5 (SMAP-5). Journal of Zhejiang University. Science. B 14 36916000
2013 Identification of discrete sites in Yip1A necessary for regulation of endoplasmic reticulum structure. PloS one 9 23342155
2023 YIPF5 (p.W218R) mutation induced primary microcephaly in rabbits. Neurobiology of disease 5 37142085
2020 YIPF5 mutations cause neonatal diabetes and microcephaly: progress for precision medicine and mechanistic understanding. The Journal of clinical investigation 5 33164987
2025 YIPF5 is an essential host factor for porcine epidemic diarrhea virus double-membrane vesicle formation. Journal of virology 3 40422075
2007 Molecular characterization of the encoding regions and tissue expression analyses for three novel porcine genes--HNRPA1, YIPF5 and UB2D2. Molecular biology reports 3 17610147
2024 Illness stress-induced transient hyperglycemia in a patient with a novel YIPF5 homozygous missense variant: expanding the phenotype. Hormones (Athens, Greece) 2 38632213
2023 Balanced chromosomal rearrangements implicate YIPF5 and SPATC1L in non-obstructive oligoasthenozoospermia and oligozoospermia and of a derivative chromosome 22 in recurrent miscarriage. Gene 1 37625567
2026 The microcephaly-associated protein YIPF5 differentially regulates ER export. iScience 0 41717013
2026 YIPFα1A expression is regulated by multilayered molecular mechanisms. FEBS open bio 0 41940818

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