ERLIN2

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.

Disorders

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