ERLIN1

ERLIN1 is an ER-resident SPFH/prohibitin-family protein that, together with ERLIN2, assembles into a large ~2 MDa ring/cage complex within cholesterol-dependent, detergent-insoluble (lipid raft-like) ER microdomains (PMID:16835267, PMID:19240031, PMID:19751772, PMID:41887216). Cryo-EM defines this complex as a 26-mer cage of alternating ERLIN1 and ERLIN2 subunits that forms a discrete luminal-leaflet microdomain and can recruit ER proteins to both its interior and exterior surfaces, secluding cargoes from their partners; each subunit carries an intramembrane phosphatidylinositol-binding pocket (PMID:41887216). Functionally, the ERLIN1/2 complex acts as a selective recognition scaffold in ER-associated degradation (ERAD): it binds activated IP3R tetramers — via the third intralumenal loop near transmembrane helix 5, with residues D2471/R2472 critical for association — as the primary upstream event that precedes polyubiquitination and proteasomal degradation (PMID:19240031, PMID:19751772, PMID:35568199). The complex bridges the E3 ubiquitin ligase RNF170 and TMUB1 through their luminal N-terminal regions binding the SPFH domain of adjacent ERLIN subunits, completing the degradation machinery (PMID:38782601). Beyond ERAD, the complex selectively binds PI(3)P and is required to maintain steady-state cellular PI(3)P levels and sustain autophagic flux, independent of VPS34 kinase activity (PMID:30135210, PMID:39018973); ERLIN1 also localizes to mitochondria-associated membranes where it interacts with AMBRA1 in a GD3- and MFN2-dependent manner to promote starvation-induced autophagosome formation (PMID:33034545). Loss of both ERLINs limits cholesterol esterification, thereby influencing ER-to-Golgi cholesterol transport, Golgi morphology and the secretory pathway (PMID:38782601). A splicing mutation in ERLIN1 (c.504+1G>A) that deletes exon 7 and disrupts the prohibitin domain causes hereditary spastic paraplegia (SPG62) (PMID:36100157).

1. 2006 High

   Established where ERLIN1 resides and how it is targeted, defining it as an ER protein that partitions into cholesterol-dependent raft-like microdomains.

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

   PMID:16835267

   Open questions at the time

   • No binding partners or molecular function identified
   • Functional role of raft partitioning not yet defined
2. 2009 High

   Showed ERLIN1 functions as a heteromeric ~2 MDa ring complex with ERLIN2 that recognizes activated IP3Rs and is required for their ERAD, defining the complex's core substrate-recognition role.

   Evidence Reciprocal Co-IP, sucrose sedimentation, EM of the complex, and RNAi with IP3R ubiquitination/degradation assays in HeLa cells

   PMID:19240031 PMID:19751772

   Open questions at the time

   • E3 ligase and ubiquitination machinery not yet identified
   • IP3R binding site on the receptor not mapped
   • Substrate selectivity mechanism unknown
3. 2009 High

   Defined the temporal logic of ERAD, placing ERLIN1/2 binding as an early, substrate-selective recognition event upstream of ubiquitination and p97 recruitment.

   Evidence Stable transfection, RNAi, Co-IP, and specificity controls (calcium mobilization, IkBa, HMG-CoA reductase ERAD) in muscarinic-receptor HeLa cells

   PMID:19751772

   Open questions at the time

   • The ligase linking recognition to ubiquitination still unidentified
   • Structural basis of complex–IP3R contact unknown
4. 2018 High

   Identified PI(3)P as a ligand of the complex and showed a disease mutation couples lipid binding to substrate engagement, linking lipid recognition to ERAD function.

   Evidence CRISPR ablation of erlin1 or erlin2, lipid-binding assays, Co-IP, and degradation assays with the erlin2 T65I mutant

   PMID:30135210

   Open questions at the time

   • Physiological consequence of PI(3)P binding not established here
   • Why erlin2 dominates IP3R binding structurally unclear
5. 2022 High

   Mapped the IP3R binding determinant to intralumenal loop 3 near TM5 and used epistasis to confirm ERLIN1/2 binding is the primary event upstream of ubiquitination.

   Evidence IP3R1 site-directed mutagenesis, Co-IP, UBE1 inhibition (TAK-243), and channel activity/degradation assays

   PMID:35568199

   Open questions at the time

   • Structure of the complex–IP3R interface not resolved
   • How binding signals ligase recruitment unknown
6. 2022 Medium

   Tied an ERLIN1 splicing mutation disrupting the prohibitin domain to hereditary spastic paraplegia (SPG62), connecting complex integrity to human disease.

   Evidence Whole-exome sequencing, minigene splicing assay, and bioinformatic analysis

   PMID:36100157

   Open questions at the time

   • Downstream functional consequence on the complex inferred, not directly measured
   • Mechanism linking ERAD defect to motor neuron degeneration unestablished
7. 2020 Medium

   Extended ERLIN1's role to autophagy by showing it acts at MAMs with AMBRA1 to drive starvation-induced autophagosome formation.

   Evidence Co-IP, FRET, siRNA of ST8SIA1/MFN2, MAM fractionation, and autophagy flux assays

   PMID:33034545

   Open questions at the time

   • Single lab
   • Molecular mechanism by which the interaction nucleates autophagosomes unclear
   • Relationship to the ERLIN1/2 ERAD complex not addressed
8. 2024 Medium

   Defined how the complex incorporates the ubiquitin ligase machinery and uncovered a role in cholesterol esterification and secretory pathway regulation.

   Evidence Proteomics, 3D structural modeling, Co-IP, and ERLIN1/2 double-KO HeLa phenotyping with cholesterol esterification assays

   PMID:38782601

   Open questions at the time

   • Single lab
   • Direct enzymatic mechanism of cholesterol esterification regulation not established
9. 2024 Medium

   Established a direct mechanistic basis for the autophagy role by showing the complex maintains steady-state PI(3)P levels independent of VPS34.

   Evidence Recombinant protein lipid binding, PI(3)P quantification in KO/knockdown cells, autophagic flux, and VPS34 activity assays

   PMID:39018973

   Open questions at the time

   • Single lab
   • Mechanism by which the complex maintains PI(3)P pools unresolved
10. 2026 High

    Resolved the complex architecture by cryo-EM as a 26-mer cage with intramembrane PI-binding pockets, providing a structural model for how it organizes microdomains and seclude cargoes.

    Evidence Single-particle cryo-EM and structural analysis of the human erlin1/2 complex

    PMID:41887216

    Open questions at the time

    • Structures of substrate- or partner-bound states not determined
    • How cage clustering is regulated unknown
11. 2019 Medium

    Implicated ERLIN1 in pathogen biology, showing it is required at distinct stages of HCV infection including initiation of RNA replication.

    Evidence siRNA knockdown with stage-specific HCV RNA, protein, and virus production readouts

    PMID:31810281

    Open questions at the time

    • Single lab
    • Direct molecular interaction with HCV components not shown
    • Whether the ERAD/microdomain function underlies this role unknown

• How the ERLIN1/2 cage's distinct functions — IP3R ERAD, PI(3)P maintenance, cholesterol handling, MAM autophagy, and substrate sequestration — are coordinated and selectively triggered remains unresolved.
• No unified model linking microdomain organization to substrate choice
• Structural basis of partner/cargo selection not determined
• In vivo physiological consequences of each function not separately tested