| Aspect | Key findings | Key sources (author year, journal) | URL/DOI |
|---|---|---|---|
| Identity/domain/localization | ERLIN2 is the verified human protein encoded by **ERLIN2** (UniProt **O94905**), an **ER lipid raft-associated** membrane protein in the **band 7/SPFH family** that hetero-oligomerizes with ERLIN1. It localizes mainly to **cholesterol-rich ER detergent-resistant nanodomains** and has also been linked to **ER–Golgi contact regions** and, under some conditions, **MAM-associated rafts** (pqac-00000003, pqac-00000008). | Veronese 2024, *Life Science Alliance*; Manganelli 2021, *Cells* | https://doi.org/10.26508/lsa.202402620 ; https://doi.org/10.3390/cells10092408 |
| Complex/partners | ERLIN2 forms large **ring-shaped ERLIN1/2 complexes** (likely ~24 subunits) that scaffold membrane proteins. Reported partners include **ERLIN1**, **RNF170**, **TMUB1**, **TMEM259**, **INSIG1**, **FAF2**, **VCP/p97**, and associations with other ERAD ligases. A 2024 study showed ERLIN scaffolds bridge **TMUB1 and RNF170** through a conserved luminal motif that binds adjacent ERLIN SPFH interfaces (pqac-00000003, pqac-00000005, pqac-00000007). | Veronese 2024, *Life Science Alliance* | https://doi.org/10.26508/lsa.202402620 |
| Pathways/mechanism | Best-supported mechanism: ERLIN2 acts as a **non-enzymatic ER membrane scaffold/adaptor** in **ER-associated degradation (ERAD)**, especially for **activated IP3 receptors (IP3Rs)**. ERLIN2 helps recruit **RNF170** for IP3R ubiquitination/degradation and binds **cholesterol** and **PI3P**, supporting microdomain assembly and client handling. ERLINs also influence **SREBP/INSIG/SCAP** regulation, **HMG-CoA reductase** turnover, and **cholesterol partitioning/esterification**, thereby affecting **Golgi morphology** and the **secretory pathway** (pqac-00000003, pqac-00000005, pqac-00000008). | Veronese 2024, *Life Science Alliance*; Manganelli 2021, *Cells* | https://doi.org/10.26508/lsa.202402620 ; https://doi.org/10.3390/cells10092408 |
| Disease links | Human genetics strongly links ERLIN2 to **SPG18 / hereditary spastic paraplegia (HSP)** with **autosomal recessive** and some **autosomal dominant** presentations. Clinical expansion includes developmental delay, seizures, contractures, hearing loss, and reported **HSP-to-ALS phenoconversion** in some families. Recent work also proposed a dominant mechanism in which mutant ERLIN2 alters IP3R control and Ca2+ homeostasis (pqac-00000004, pqac-00000006, pqac-00000001, pqac-00000000). | Cioffi 2024, *Neurological Sciences*; Zhu 2023, *Human Mutation*; Trinchillo 2024, *Neurological Sciences*; Open Targets | https://doi.org/10.1007/s10072-024-07423-w ; https://doi.org/10.1155/2023/4834423 ; https://doi.org/10.1007/s10072-024-07500-0 ; https://platform.opentargets.org/target/ENSG00000147475 |
| Key quantitative findings | Explicit quantitative snippets reported in accessible evidence: **HeLa ERLIN double-knockout** cells showed a tendency toward increased **SOAT1** abundance (**log2FC = 0.40; q = 0.07**), consistent with increased cholesterol esterification pressure; in one 2024 SPG18 clinical series, **2 of 5 cases** showed **HSP→ALS phenoconversion**; the same report noted **944 clinically suspected HSP patients screened over 8 years** in one laboratory workflow (pqac-00000005, pqac-00000004). | Veronese 2024, *Life Science Alliance*; Cioffi 2024, *Neurological Sciences* | https://doi.org/10.26508/lsa.202402620 ; https://doi.org/10.1007/s10072-024-07423-w |
| 2023–2024 mechanistic update | A 2023 patient-derived iPSC study of **ERLIN2 p.Val71Ala** proposed that mutant ERLIN2 recruits **RNF213** to drive **IP3R1 degradation**, lowering intracellular free **Ca2+**, triggering **ER-stress apoptosis**, and suppressing **MAPK signaling/cell proliferation**. A 2024 cell-biology study extended ERLIN function beyond classical ERAD, showing ERLIN scaffolds **restrict cholesterol esterification** and favor **ER-to-Golgi cholesterol transport** to support secretory-pathway organization (pqac-00000006, pqac-00000003). | Zhu 2023, *Human Mutation*; Veronese 2024, *Life Science Alliance* | https://doi.org/10.1155/2023/4834423 ; https://doi.org/10.26508/lsa.202402620 |


*Table: This table summarizes the core functional annotation evidence for human ERLIN2, emphasizing verified identity, molecular mechanism, disease relevance, and the most explicit quantitative findings from recent literature.*