Affinage

ERLIN1

Erlin-1 · UniProt O75477

Length
348 aa
Mass
39.2 kDa
Annotated
2026-04-28
18 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERLIN1 is a core subunit of the ER-resident erlin1/2 complex, a 26-subunit (13 heterodimer) ring-shaped cage that organizes cholesterol-rich, lipid raft-like microdomains on the ER membrane to coordinate substrate recognition for ER-associated degradation, lipid homeostasis, and autophagy. The complex recognizes activated IP3 receptors by binding their intralumenal loop 3, acting upstream of polyubiquitination to initiate IP3R ERAD, and scaffolds the E3 ligase RNF170 via TMUB1, physically sequestering substrates within the cage interior (PMID:19240031, PMID:35568199, PMID:41887216, PMID:38782601). ERLIN1/2 selectively binds phosphatidylinositol 3-phosphate through intramembrane phosphoinositide-binding pockets in each subunit, stabilizing cellular PI(3)P pools to sustain autophagic flux independently of VPS34 kinase activity, and interacts with AMBRA1 at mitochondria-associated membranes to promote autophagosome formation (PMID:39018973, PMID:30135210, PMID:33034545). Loss of erlin1/2 also limits cholesterol esterification, redirecting cholesterol to the Golgi and altering secretory pathway organization (PMID:38782601).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2006 High

    Establishing ERLIN1's subcellular localization resolved where the protein operates: in cholesterol-dependent, detergent-resistant ER membrane microdomains, with its N-terminus sufficient for ER targeting without classical retrieval motifs.

    Evidence Sucrose gradient fractionation, cholesterol depletion, GFP-fusion targeting in mammalian cells

    PMID:16835267

    Open questions at the time
    • No function or binding partners identified at this stage
    • Mechanism of cholesterol-dependent raft association undefined
  2. 2009 High

    Discovery that ERLIN1 and ERLIN2 form a ~2 MDa ring-shaped complex that binds activated IP3Rs upstream of polyubiquitination established the complex as a substrate recognition scaffold in a selective ERAD pathway.

    Evidence Native gel/EM structural analysis, RNAi depletion, co-IP, ubiquitination/degradation assays with selective substrate controls (IP3R vs. IκBα vs. HMG-CoA reductase)

    PMID:19240031 PMID:19751772

    Open questions at the time
    • Binding interface on IP3R not mapped
    • Identity of ubiquitin ligase recruited by the complex unknown
    • Stoichiometry and subunit arrangement unresolved
  3. 2018 High

    Demonstrating that ERLIN2 is the dominant IP3R-binding subunit and that the complex selectively binds PI(3)P revealed a lipid-binding function and clarified individual subunit contributions.

    Evidence Gene editing (erlin1/erlin2 KO), in vitro lipid-binding assays with recombinant proteins, T65I mutagenesis linked to spastic paraplegia

    PMID:30135210

    Open questions at the time
    • Structural basis of PI(3)P binding unknown
    • Functional consequence of PI(3)P binding on autophagy not yet tested
  4. 2019 Medium

    ERLIN1 was identified as a host factor required for HCV RNA replication at a post-entry step, extending its functional scope beyond ERAD to viral exploitation of ER membrane platforms.

    Evidence siRNA knockdown in HCV-infected cells with stepwise mechanistic dissection

    PMID:31810281

    Open questions at the time
    • Mechanism of ERLIN1 contribution to viral replication complex assembly unknown
    • Single-lab finding without independent replication
  5. 2020 Medium

    Linking ERLIN1 to AMBRA1 at MAMs established a role in starvation-induced autophagosome formation dependent on ganglioside GD3 and MFN2, connecting the complex to autophagy initiation.

    Evidence FRET, co-IP, siRNA knockdown of ERLIN1/ST8SIA1/MFN2, LC3-II flux assays, MAM fractionation

    PMID:33034545

    Open questions at the time
    • Direct vs. indirect nature of ERLIN1–AMBRA1 interaction unclear
    • Relationship between PI(3)P binding and MAM autophagy function not tested
  6. 2022 High

    Mapping the erlin1/2 binding site to IP3R1 intralumenal loop 3 (D2471/R2472) and showing that ubiquitin-activating enzyme inhibition does not disrupt this binding definitively placed erlin complex recognition as the initiating event in IP3R ERAD.

    Evidence Site-directed mutagenesis of IP3R1, co-IP, TAK-243 pharmacological dissection

    PMID:35568199

    Open questions at the time
    • How IP3R activation exposes the loop 3 binding site is undefined
    • No structural model of the erlin–IP3R interface
  7. 2024 High

    Two parallel advances clarified downstream functions: direct PI(3)P binding by the complex stabilizes ~50% of cellular PI(3)P to sustain autophagic flux independently of VPS34, while loss of erlin1/2 limits cholesterol esterification, promoting ER-to-Golgi cholesterol transport and reshaping Golgi morphology.

    Evidence Recombinant PI(3)P binding assays, erlin1/2 KO with PI(3)P quantification and autophagy readouts (PMID:39018973); double-KO HeLa cells with lipidomics, cholesterol transport assays, co-IP mapping TMUB1–RNF170 scaffold (PMID:38782601)

    PMID:38782601 PMID:39018973

    Open questions at the time
    • Structural basis for PI(3)P sequestration within the cage not resolved at atomic level
    • Mechanism linking cholesterol esterification to erlin complex presence is correlative
  8. 2025 High

    Cryo-EM structures revealed the 26-mer cage architecture (13 erlin1/2 heterodimers) with intramembrane phosphoinositide-binding pockets and demonstrated physical sequestration of TMUB1 cargo within the cage, providing the structural framework for all previously described functions.

    Evidence Single-particle cryo-EM at near-atomic resolution with functional validation of cargo caging

    PMID:41887216

    Open questions at the time
    • Structure of the complete erlin–IP3R–RNF170 degradation complex not determined
    • Dynamics of cage assembly/disassembly in response to stimuli unknown
    • Mechanism by which cage clustering creates larger microdomains needs characterization

Open questions

Synthesis pass · forward-looking unresolved questions
  • Outstanding questions include how the erlin cage dynamically remodels upon substrate engagement, whether PI(3)P binding and IP3R ERAD functions are coordinated or independent within the same cage, and how erlin1 vs. erlin2 subunit contributions specify distinct substrate selectivities.
  • No time-resolved structural data on cage dynamics during ERAD
  • Relationship between PI(3)P stabilization and ERAD substrate processing within the cage unclear
  • In vivo physiological consequences of erlin1 loss vs. erlin2 loss not systematically compared in animal models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 3 GO:0140313 molecular sequestering activity 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-9612973 Autophagy 2 R-HSA-382551 Transport of small molecules 1
Partners
AMBRA1ERLIN2ITPR1RNF170TMUB1
Complex memberships
erlin1/erlin2 26-mer cage complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 ERLIN1 (KE04p) localizes to the ER membrane and is enriched in detergent-insoluble, buoyant (lipid raft-like) fractions in a cholesterol-dependent manner. The extreme N-terminus of ERLIN1 is sufficient for ER targeting in the absence of classical ER retrieval motifs. Sucrose gradient fractionation, cholesterol depletion, GFP fusion/heterologous targeting, confocal microscopy Journal of cell science High 16835267
2009 ERLIN1 (SPFH1) and ERLIN2 (SPFH2) form a ~2 MDa heteromeric ring-shaped ER membrane complex that binds activated IP3R tetramers prior to their polyubiquitination and is required for IP3R ERAD; RNAi-mediated depletion of SPFH1/2 blocks IP3R polyubiquitination and degradation. Native gel/electron microscopy (ring-shaped complex), RNA interference, co-immunoprecipitation, ubiquitination and degradation assays The Journal of biological chemistry High 19240031 19751772
2009 The ERLIN1/2 (SPFH1/2) complex associates with activated IP3Rs before polyubiquitination and before p97 recruitment, placing it upstream of ubiquitination in the ERAD cascade; its depletion selectively blocks IP3R ERAD but not IκBα processing or HMG-CoA reductase ERAD. RNA interference, co-immunoprecipitation, proteasome inhibitor/pulse-chase degradation assays, calcium mobilization measurement Biochimica et biophysica acta High 19751772
2018 ERLIN2 is the dominant subunit in mediating the erlin1/2 complex interaction with IP3Rs; the spastic paraplegia-linked erlin2 T65I mutation dramatically inhibits IP3R interaction and IP3R polyubiquitination/degradation. The erlin1/2 complex selectively binds phosphatidylinositol 3-phosphate (PI(3)P), with erlin2 binding more strongly than erlin1, and the T65I mutation inhibits this PI(3)P binding. Gene editing (erlin1 or erlin2 ablation), co-immunoprecipitation, ubiquitination/degradation assays, lipid-binding assays with recombinant proteins, site-directed mutagenesis The Journal of biological chemistry High 30135210
2020 ERLIN1 interacts with AMBRA1 at MAM (mitochondria-associated membrane) raft-like microdomains, and this interaction is required for autophagosome formation upon nutrient starvation; the interaction depends on ganglioside GD3 (ST8SIA1) and MFN2 integrity. Co-immunoprecipitation, FRET, siRNA knockdown of ERLIN1/ST8SIA1/MFN2, autophagy flux assays (LC3-II, SQSTM1), subcellular fractionation to isolate MAMs Autophagy Medium 33034545
2022 The erlin1/2 complex binds to IP3R1 intralumenal loop 3 (IL3), specifically a region close to TM5 (amino acids D2471/R2472); mutation of these residues blocks erlin1/2 complex association. UBE1 inhibition blocks IP3R1 ubiquitination/degradation without altering erlin1/2 complex association, confirming erlin1/2 binding is the primary initiating event preceding ubiquitination. Site-directed mutagenesis of IP3R1, co-immunoprecipitation, small-molecule inhibitor (TAK-243) treatment, Ca2+ channel activity assays The Journal of biological chemistry High 35568199
2024 The erlin1/2 complex directly and selectively binds PI(3)P; loss or disruption of the complex reduces cellular PI(3)P levels by ~50%, which correlates with decreased autophagic flux without affecting VPS34 kinase activity or the endocytic pathway. In vitro PI(3)P binding with recombinant erlins, PI(3)P quantification in cells with E1/E2 KO, autophagic flux assays, VPS34 activity assay, pharmacological PI(3)P depletion Biochemical and biophysical research communications High 39018973
2024 ERLIN1/2 scaffolds mediate the interaction between the full-length isoform of TMUB1 and RNF170 via a luminal N-terminal conserved region in TMUB1 and RNF170 that contacts the SPFH domain of adjacent ERLIN subunits. Loss of both ERLINs limits cholesterol esterification, thereby promoting cholesterol transport from ER to Golgi and regulating Golgi morphology and the secretory pathway. Co-immunoprecipitation, 3D structural modelling, proteomic (omics) analysis, phenotypic characterization of ERLIN1/2 double-KO HeLa cells, cholesterol transport assays Life science alliance High 38782601
2019 ERLIN1 is required for HCV RNA replication and infectious virus production; siRNA silencing of erlin1 reduces intracellular HCV RNA, protein expression, and virus production, with the requirement mapping to a step after cell entry and primary translation but before/during RNA replication. siRNA knockdown, HCV infection assays, RNA quantification, protein expression analysis, mechanistic step mapping Cells Medium 31810281
2025 Cryo-EM structure of the human erlin1/2 complex reveals a 26-mer cage assembly (13 heterodimers of erlin1 and erlin2), defining a nanometer-sized microdomain on the ER luminal leaflet. Each subunit contains an intramembrane phosphatidylinositol-binding pocket. The complex can cage substrate proteins (e.g., recruiting TMUB1 to interior and exterior of cage), physically secluding them from binding partners; individual cages can cluster to form microdomains of different sizes. Single-particle cryo-EM, structural modelling, functional validation of cargo sequestration Molecular cell High 41887216
2025 Cryo-EM structures of the ER-resident erlin1/2 complex show it assembles as 13 heterodimers (26-mer), with defined inter-subunit interfaces; key interactions underlying the architecture were described and conformational properties elucidated. Single-particle cryo-EM bioRxivpreprint Medium bio_10.1101_2025.04.21.649849
2025 ERLIN1 interacts directly with CYP1A2 via their ER N-terminal signal-anchor domains within detergent-resistant ER membrane microdomains/MAMs; siRNA knockdown of erlin-1 relocates CYP1A2 from DRMs to non-DRMs and impairs its ER-to-lysosomal-associated degradation (ERLAD), resulting in insoluble CYP1A2 aggregates. This ERLAD requirement is rescued by re-expression of erlin-1 or just its N-terminal 1–30 residue signal-anchor domain. SURF split-fluorogenic complementation assay (protein-protein interaction), siRNA knockdown, subcellular fractionation (DRM isolation), rescue with siRNA-resistant constructs, CYP2B1 as proof-of-concept bioRxivpreprint Medium bio_10.1101_2025.09.25.678692

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins that define lipid-raft-like domains of the ER. Journal of cell science 195 16835267
2009 An endoplasmic reticulum (ER) membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate receptors. The Journal of biological chemistry 92 19240031
2020 Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs. Autophagy 69 33034545
2013 The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study. Atherosclerosis 42 23477746
2018 ERLIN1 mutations cause teenage-onset slowly progressive ALS in a large Turkish pedigree. European journal of human genetics : EJHG 30 29453415
2018 The erlin2 T65I mutation inhibits erlin1/2 complex-mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3-phosphate binding. The Journal of biological chemistry 26 30135210
2009 SPFH1 and SPFH2 mediate the ubiquitination and degradation of inositol 1,4,5-trisphosphate receptors in muscarinic receptor-expressing HeLa cells. Biochimica et biophysica acta 23 19751772
2022 A novel homozygous mutation in ERLIN1 gene causing spastic paraplegia 62 and literature review. European journal of medical genetics 10 36100157
2022 Binding of the erlin1/2 complex to the third intralumenal loop of IP3R1 triggers its ubiquitin-proteasomal degradation. The Journal of biological chemistry 8 35568199
2019 The Host Factor Erlin-1 is Required for Efficient Hepatitis C Virus Infection. Cells 8 31810281
2024 The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD. Med (New York, N.Y.) 6 38776916
2021 Transcriptome and Literature Mining Highlight the Differential Expression of ERLIN1 in Immune Cells during Sepsis. Biology 6 34439987
2000 Identification and characterization of a novel gene KE04 differentially expressed by activated human dendritic cells. Biochemical and biophysical research communications 6 11118313
2024 ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway. Life science alliance 4 38782601
2024 Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis. Human genetics 3 39367212
2024 The erlin1/erlin2 complex binds to and stabilizes phosphatidylinositol 3-phosphate and regulates autophagy. Biochemical and biophysical research communications 2 39018973
2026 The Erlin1/2 complex is a dynamic scaffold for membrane microdomain assembly on the endoplasmic reticulum. Molecular cell 0 41887216
2025 ERLIN1: A central regulator of protein quality control, lipid homeostasis, and cellular signaling at the endoplasmic reticulum. Cellular signalling 0 41205880