# ERLIN2 (SPFH2 / ER lipid raft-associated protein 2) review notes

UniProt: O94905 (ERLN2_HUMAN), 339 aa. Synonyms SPFH2, C8orf2. HGNC:1356.
Single-pass type II ER membrane protein with a lumenal SPFH/prohibitin (band 7) domain. Band 7/mec-2
family; associates with lipid-raft-like ER domains. Disease: hereditary spastic paraplegia SPG18A/SPG18B
and recessive intellectual disability/joint-contractures syndrome.

## Core biology
1. **ERLIN1/ERLIN2 complex mediating ERAD of IP3 receptors.** SPFH2 (ERLIN2) and SPFH1 (ERLIN1) form a
   ~2 MDa ring-shaped ER membrane complex that binds IP3R tetramers and mediates their ERAD with RNF170.
   [PMID:19240031 "the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex that binds to IP(3)R tetramers"]
   SPFH2 alone was shown to mediate ERAD of IP3 receptors and other substrates (PubMed:17502376, not cached).
   In complex with ERLIN1, interacts with RNF170. ComplexPortal CPX-7121.
2. **Sterol-accelerated ERAD of HMGCR (gp78/AMFR module).** ERLIN2 promotes sterol-accelerated ERAD of
   HMG-CoA reductase via an AMFR/gp78-containing ubiquitin ligase complex; TMUB1 bridges ERLIN2 to gp78.
   [PMID:21343306 "we identify two ER membrane proteins, SPFH2 and TMUB1, as associated proteins of mammalian gp78"]
   Interacts with AMFR, SYVN1, RNF139, TMUB1, HMGCR.
3. **Cholesterol binding / SREBP regulation.** Like ERLIN1, ERLIN2 restricts SREBP activation and
   regulates cholesterol homeostasis; interacts with SCAP, INSIG1, SREBF1, SREBF2 under sterol sufficiency.
   [PMID:24217618 "Erlins bound cholesterol with specificity and strong cooperativity"]
4. **E3-ligase binding.** ERLIN2 binds the ER ubiquitin ligases RNF170, AMFR/gp78, SYVN1, RNF139, and the
   RNF185/RNF5 module (PubMed:24019521) — informative ubiquitin protein ligase binding.
5. **Lipid-raft ER domains** (PMID:16835267).

## Annotation assessment summary
- ER membrane (GO:0005789) / ER (GO:0005783): core compartment → ACCEPT.
- ERLIN1/2 complex / ERAD of IP3R (GO:0036503 ERAD pathway IDA): core → ACCEPT.
- cholesterol binding (GO:0015485 IBA): core MF → ACCEPT (note: only IBA here, no human IDA, but consistent
  with the erlin family cholesterol-binding evidence in PMID:24217618).
- SREBP signaling / negative regulation cholesterol & fatty acid biosynthesis / regulation cholesterol
  biosynthesis: SREBP/sterol role → ACCEPT.
- ubiquitin protein ligase binding (GO:0031625 IPI PMID:24019521; IEA InterPro): binds RNF185/RNF5 and other
  ER E3 ligases → ACCEPT (informative).
- membrane raft (GO:0045121 IDA/NAS): lipid-raft ER domains → KEEP_AS_NON_CORE.
- **plasma membrane (GO:0005886) TAS Reactome (x13, FGFR1 signaling pathways)**: ERLIN2 is an ER membrane
  protein; plasma-membrane localization is an over-annotation from pathway bulk-membrane curation →
  MARK_AS_OVER_ANNOTATED.
- protein-containing complex (GO:0032991): generic → KEEP_AS_NON_CORE.
- protein binding (GO:0005515) IPI: uninformative → KEEP_AS_NON_CORE (TMEM41B interaction PMID:30352685 etc.).
- Do NOT over-claim catalytic MF: ERLIN2 is a scaffold/lipid-binding SPFH protein.

## Falcon deep-research findings (incorporated 2026-06)

All four cited papers below were PMID-verified via PubMed (DOI-to-PMID); none are in the
publications/ cache, so no verbatim supporting_text was added to the review — references
added with reference_review only, plus the Veronese ref id on the E3-ligase/TMUB1 core_function.

- ERLIN1/2 scaffolds form "large ring-like cup-shaped structures on the ER membrane" that
  "bind cholesterol and E3 ubiquitin ligases, potentially defining functional nanodomains."
  [PMID:38782601 "ERLIN1 and ERLIN2 ... form large ring-like cup-shaped structures on the endoplasmic reticulum (ER) membrane and serve as platforms to bind cholesterol and E3 ubiquitin ligases"]
- New mechanistic link: ERLIN scaffolds bridge full-length TMUB1 and RNF170 through a conserved
  luminal N-terminal motif that binds the SPFH/prohibitin domain of two adjacent ERLIN subunits;
  HSP-linked variants map to these interfaces.
  [PMID:38782601 "ERLIN scaffolds mediate the interaction between the full-length isoform of TMUB1 ... and RNF170 ... binds the stomatin/prohibitin/flotillin/HflKC domain of two adjacent ERLIN subunits at different interfaces. Protein variants that preclude these interactions have been previously linked to hereditary spastic paraplegia"]
- New cell-biology role beyond classical ERAD: ERLINs limit cholesterol esterification, favouring
  ER-to-Golgi cholesterol transport and regulating Golgi morphology and the secretory pathway
  (HeLa double-KO phenotype).
  [PMID:38782601 "a role of ERLIN scaffolds in limiting cholesterol esterification, thereby favouring cholesterol transport from the ER to the Golgi apparatus and regulating Golgi morphology and the secretory pathway"]
- Falcon also notes SOAT1 inhibition (avasimibe) rescues lipid-droplet/Golgi phenotypes in
  ERLIN-deficient cells (from figures); treat as a translational/pharmacology lead, not a GO
  annotation. (Veronese 2024, PMID:38782601)
- Proposed dominant disease mechanism: a heterozygous ERLIN2 p.Val71Ala recruits the E3 ligase
  RNF213 (NOT RNF170) to degrade IP3R1, lowering free Ca2+, triggering ER-stress apoptosis and
  suppressing MAPK/proliferation in patient-derived iPSC models.
  [PMID:40225166 "the ERLIN2 heterozygous missense variant protein recruited the ubiquitin E3 ligase RNF213 to degrade IP3R1 ... reduction of intracellular free calcium, which triggered endoplasmic reticulum (ER) stress-mediated apoptosis"]
- SPG18 inheritance is broader than classic recessive: monoallelic/autosomal-dominant ERLIN2
  variants (often pure, late-onset) occur, with HSP-to-ALS phenoconversion (2/5 cases) and a
  recurrent monoallelic c.502G>A hotspot for an ALS-like phenotype.
  [PMID:38427163 "Recent cases of late-onset, pure HSP with monoallelic ERLIN2 variants ... two cases out of five exhibiting HSP-ALS phenoconversion ... relatively high incidence of the c.502G>A variant in monoallelic SPG18 cases"]
- An AD ERLIN2 p.V168M family showed variable expressivity (ALS phenoconversion, pure HSP, and a
  complicated form with psychomotor delay/epilepsy) but NORMAL erlin2 oligomerization, arguing
  against a dominant-negative oligomerization defect for this variant.
  [PMID:38607533 "a phenoconversion to amyotrophic lateral sclerosis (ALS) ... pure HSP ... a complicated form with psychomotor delay and epilepsy ... Erlin2 oligomerization was found to be normal ... we ruled out a dominant negative effect of V168M on erlin2 oligomerization"]
- Caveat: the Falcon report's "cryo-EM of the ERLIN complex" framing is not directly supported by
  a retrieved structural paper; Veronese 2024 uses 3D modelling, not cryo-EM. The existing
  suggested_question about a cryo-EM-resolved architecture remains a forward-looking question.