Erlin1, also known as endoplasmic reticulum lipid raft associated 1, forms complexes with Erlin2 on the endoplasmic reticulum (ER) membrane, creating ring-like cup-shaped structures. These complexes act as platforms to bind cholesterol and E3 ubiquitin ligases, potentially defining functional nanodomains. They are involved in multiple cellular processes, including cholesterol metabolism, the secretory pathway, autophagy, and are associated with neurodegenerative diseases [1,3,5].

In functional studies, Erlin1/2 scaffolds were found to mediate the interaction between TMUB1 and RNF170, and limit cholesterol esterification, thus regulating cholesterol transport from the ER to the Golgi apparatus and the secretory pathway [1]. In autophagy research, knocking down ERLIN1 gene expression impaired the interaction between AMBRA1 and ERLIN1 at mitochondria-associated membranes (MAMs), hindering autophagosome formation [3]. Also, the disruption or deletion of the Erlin1/2 complex reduced phosphatidylinositol 3-phosphate (PI(3)P) levels in HeLa cells, correlating with a decrease in autophagic flux [5]. Mutations in ERLIN1 have been linked to hereditary spastic paraplegia (SPG62), and a series of 13 individuals with biallelic ERLIN1 variants presented with childhood-onset paraparesis, with possible cerebellar and peripheral nerve involvement [2,4]. Additionally, the ERLIN1 p.Ile291Val variant is associated with protection against metabolic dysfunction-associated steatotic liver disease (MASLD) [6].

In conclusion, Erlin1 is crucial for maintaining cellular lipid homeostasis, autophagy regulation, and is significantly associated with neurodegenerative and metabolic diseases. Gene-knockout or conditional-knockout mouse models, if available in the future, could further clarify its role in these biological processes and diseases, providing new insights into potential therapeutic strategies for related disorders.

References:

1. Veronese, Matteo, Kallabis, Sebastian, Kaczmarek, Alexander Tobias, Krüger, Marcus, Rugarli, Elena I. 2024. ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway. In Life science alliance, 7, . doi:10.26508/lsa.202402620. https://pubmed.ncbi.nlm.nih.gov/38782601/

2. Zhu, Ze-Yu, Li, Zi-Yi, Zhang, Chao, Tian, Wo-Tu, Cao, Li. 2022. A novel homozygous mutation in ERLIN1 gene causing spastic paraplegia 62 and literature review. In European journal of medical genetics, 65, 104608. doi:10.1016/j.ejmg.2022.104608. https://pubmed.ncbi.nlm.nih.gov/36100157/

3. Manganelli, Valeria, Matarrese, Paola, Antonioli, Manuela, Sorice, Maurizio, Garofalo, Tina. 2020. Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs. In Autophagy, 17, 2528-2548. doi:10.1080/15548627.2020.1834207. https://pubmed.ncbi.nlm.nih.gov/33034545/

4. Cogan, Guillaume, Zaki, Maha S, Issa, Mahmoud, de Sainte Agathe, Jean-Madeleine, Mignot, Cyril. 2024. Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis. In Human genetics, 143, 1353-1362. doi:10.1007/s00439-024-02702-0. https://pubmed.ncbi.nlm.nih.gov/39367212/

5. Hua, Fanghui, Bonzerato, Caden G, Keller, Katherine R, Luo, Juntao, Wojcikiewicz, Richard J H. 2024. The erlin1/erlin2 complex binds to and stabilizes phosphatidylinositol 3-phosphate and regulates autophagy. In Biochemical and biophysical research communications, 731, 150397. doi:10.1016/j.bbrc.2024.150397. https://pubmed.ncbi.nlm.nih.gov/39018973/

6. Rendel, Miriam Daphne, Vitali, Cecilia, Creasy, Kate Townsend, Rader, Daniel J, Schneider, Carolin Victoria. 2024. The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD. In Med (New York, N.Y.), 5, 963-980.e5. doi:10.1016/j.medj.2024.04.010. https://pubmed.ncbi.nlm.nih.gov/38776916/