ERLIN2 PN Consistency Notes
- Generated: 2026-06-18
- Project: PROTEOSTASIS
- Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
- UniProt: O94905
- AIGR review status: COMPLETE
- Review batch: proteostasis-batch-2026-06-11
- Batch change status: added
Source Files Checked
Deep Research Files
AIGR Review Snapshot
- Description: ERLIN2 (SPFH2, ER lipid raft-associated protein 2) is a single-pass type II endoplasmic reticulum (ER) membrane protein with a lumenal SPFH/prohibitin (band 7) domain, belonging to the band 7/mec-2 (stomatin-prohibitin-flotillin) family. It associates with lipid-raft-like domains of the ER membrane and functions as a scaffold rather than an enzyme. ERLIN2 forms a large ring-shaped heteromeric complex with its homolog ERLIN1 (SPFH1); the ERLIN1/ERLIN2 complex binds inositol 1,4,5-trisphosphate receptor (IP3R) tetramers and, together with the ER ubiquitin ligase RNF170, mediates the ER-associated degradation (ERAD) of activated IP3Rs, controlling calcium signaling. ERLIN2 also promotes sterol-accelerated ERAD of HMG-CoA reductase through an AMFR/gp78-containing ubiquitin ligase complex (with TMUB1 bridging ERLIN2 to gp78), and it binds cholesterol and restricts SREBP activation by associating with the SCAP-SREBP-Insig machinery, thereby negatively regulating cholesterol and fatty acid biosynthesis. Through these activities it recruits and binds multiple ER ubiquitin ligases (RNF170, AMFR/gp78, SYVN1, RNF139, RNF185/RNF5). Loss-of-function variants in ERLIN2 cause hereditary spastic paraplegia (SPG18A/SPG18B) and a recessive intellectual disability syndrome.
- Existing/core annotation action counts: ACCEPT: 29; KEEP_AS_NON_CORE: 10; MARK_AS_OVER_ANNOTATED: 12
PN Consistency Summary
- Consistency: Strong. Deep research (Veronese 2024 scaffold/TMUB1-RNF170; Zhu 2023 iPSC Ca2+/IP3R1; Cioffi/Trinchillo 2024 SPG18) ↔ review YAML (ERAD of IP3R + HMGCR via gp78/AMFR, cholesterol binding, SREBP restriction, E3-ligase binding RNF170/AMFR/SYVN1/RNF139/RNF185-RNF5, membrane raft) ↔ PN annotation all agree. No contradictions.
- PN story / NEW pressure: PN asserts ERAD + non-catalytic E3-complex membership — both already captured (GO:0036503 IDA PMID:19240031; GO:0031625 ubiquitin protein ligase binding has an experimental IPI PMID:24019521, stronger than ERLIN1). Sterol-accelerated HMGCR ERAD (PMID:21343306) and the 2024 scaffold/cholesterol-esterification role (PMID:38782601) extend beyond GOA but are cited. No NEW term forced; optional MF ADD GO:0160072 "ubiquitin ligase complex scaffold activity" (verified real). Verdict: already captured; scaffold-activity term optional.
- Evidence alignment: PN cites opaque workbook IDs (1610068, 41481136 — not PMIDs). Review anchors to PMID:19240031, 24217618, 21343306, 24019521, 38782601, 40225166 + ComplexPortal CPX-7121. Note review flags RNF213 (Zhu/PMID:40225166) as a mutant-context ligase distinct from canonical RNF170 — correctly not conflated.
- Verdict: Consistent and high-quality; PN story already captured. GO:0000151 projection mildly over-reaches (non-catalytic scaffold); prefer GO:0000835 / GO:0160072. PM over-annotation correctly handled.
Full Consistency Review
- UniProt: O94905 (ERLN2_HUMAN, SPFH2; 3 isoforms) · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE (all actioned; 11 plasma-membrane Reactome annotations MARK_AS_OVER_ANNOTATED).
- PN placement:
ER proteostasis|Organelle-specific protein degradation|ER associated degradation|ER handling of ERAD substrates and Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|RNF170 / ERLIN complex|noncatalytic / BAND 7 ; PN-node mapping: [group ERAD] mapped/exact GO:0036503; [type ER-handling] mapped/ok_for_propagation GO:0036503; [group idiosyncratic RING complex] mapped/ok_for_propagation GO:0000151 ubiquitin ligase complex; subtype/type/branch no_mapping; UPS class context_only/too_broad GO:0061630. (Dossier identical to ERLIN1.)
- Consistency: Strong. Deep research (Veronese 2024 scaffold/TMUB1-RNF170; Zhu 2023 iPSC Ca2+/IP3R1; Cioffi/Trinchillo 2024 SPG18) ↔ review YAML (ERAD of IP3R + HMGCR via gp78/AMFR, cholesterol binding, SREBP restriction, E3-ligase binding RNF170/AMFR/SYVN1/RNF139/RNF185-RNF5, membrane raft) ↔ PN annotation all agree. No contradictions.
- PN story / NEW pressure: PN asserts ERAD + non-catalytic E3-complex membership — both already captured (GO:0036503 IDA PMID:19240031; GO:0031625 ubiquitin protein ligase binding has an experimental IPI PMID:24019521, stronger than ERLIN1). Sterol-accelerated HMGCR ERAD (PMID:21343306) and the 2024 scaffold/cholesterol-esterification role (PMID:38782601) extend beyond GOA but are cited. No NEW term forced; optional MF ADD GO:0160072 "ubiquitin ligase complex scaffold activity" (verified real). Verdict: already captured; scaffold-activity term optional.
- Mapping strategy: Same as ERLIN1 — ERAD mapping correct; GO:0000151 over-reaches (catalytic-complex CC projected onto non-catalytic BAND 7 scaffold). Prefer GO:0000835 "ER ubiquitin ligase complex" (verified real). Distinct from ERLIN1: the plasma-membrane annotations are correctly MARK_AS_OVER_ANNOTATED (Reactome FGFR1 bulk-membrane curation), consistent with ER-membrane SPFH biology — handled well, no change needed.
- Evidence alignment: PN cites opaque workbook IDs (1610068, 41481136 — not PMIDs). Review anchors to PMID:19240031, 24217618, 21343306, 24019521, 38782601, 40225166 + ComplexPortal CPX-7121. Note review flags RNF213 (Zhu/PMID:40225166) as a mutant-context ligase distinct from canonical RNF170 — correctly not conflated.
- Verdict: Consistent and high-quality; PN story already captured. GO:0000151 projection mildly over-reaches (non-catalytic scaffold); prefer GO:0000835 / GO:0160072. PM over-annotation correctly handled.
Recommended edits: [MAP] Replace/qualify the GO:0000151 group projection with GO:0000835 "ER ubiquitin ligase complex" (CC), noting ERLINs are non-catalytic BAND 7 subunits. [YAML, optional] Consider adding MF GO:0160072 "ubiquitin ligase complex scaffold activity" to core_functions.
PN Dossier Context
- review_batch: proteostasis-batch-2026-06-11
- review_yaml: genes/human/ERLIN2/ERLIN2-ai-review.yaml
- PN workbook rows: 2
PN row 1: ER proteostasis | Organelle-specific protein degradation | ER associated degradation | ER handling of ERAD substrates
- UniProt: O94905
- In branches: ER, UPS
- PN-node mapping records (path + ancestors):
- [type] ER proteostasis|Organelle-specific protein degradation|ER associated degradation|ER handling of ERAD substrates
status=mapped scope=ok_for_propagation_to_go GO=[GO:0036503 ERAD pathway]
rationale: This PN type captures ER-lumenal and membrane-local ERAD handling steps prior to retrotranslocation. These steps are mechanistic parts of the broader ERAD pathway, so propagation to ERAD pathway is appropriate.
- [group] ER proteostasis|Organelle-specific protein degradation|ER associated degradation
status=mapped scope=exact GO=[GO:0036503 ERAD pathway]
rationale: The PN group "ER associated degradation" is a direct lexical and biological match to the GO ERAD pathway term. The additional branch and class context disambiguates the source string from any broader degradation language.
- [class] ER proteostasis|Organelle-specific protein degradation
status=no_mapping scope= GO=[]
rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
status=no_mapping scope= GO=[]
rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.
PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | idiosyncratic RING complex | RNF170 / ERLIN complex | noncatalytic / BAND 7
- UniProt: O94905
- In branches: ER, UPS
- Signature domains: (none)
- Auxiliary domains: IPR001107
- PN references (titles):
- PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|RNF170 / ERLIN complex|noncatalytic / BAND 7
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|RNF170 / ERLIN complex
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex
status=mapped scope=ok_for_propagation_to_go GO=[GO:0000151 ubiquitin ligase complex]
rationale: This PN group is an E3 ligase complex bucket. The safest shared GO target is ubiquitin ligase complex membership rather than assigning catalytic activity to every subunit.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
status=no_mapping scope= GO=[]
rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.
Projected GO annotations (3)
- GO:0036503 ERAD pathway | scope=exact | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation
- GO:0036503 ERAD pathway | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation|ER handling of ERAD substrates
- GO:0000151 ubiquitin ligase complex | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex
Note
This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.