The ERLINs as endoplasmic reticulum membrane scaffolds and their role in hereditary spastic paraplegia

• Applicant: Professorin Dr. Elena Irene Rugarli
• Subject Area: Cell Biology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 387639709

ERLIN1 and ERLIN2 are homologous proteins of about 40 kDa that assemble in hetero-oligomeric or homo-oligomeric high-molecular weight complexes. ERLINs belong to the SPFH family of proteins, which have been proposed to organize membrane microdomains with distinct lipid and protein composition. The ERLINs localize to the endoplasmic reticulum (ER), bind cholesterol, and promote ER-associated degradation of specific substrates. Loss-of-function mutations in ERLIN1 and ERLIN2 genes have been found in patients affected by hereditary spastic paraplegia (HSP), a genetically heterogeneous neurological disease characterized by progressive degeneration of central motor axons. How lack of ERLINs leads to HSP remains enigmatic. We propose that, as crucial protein and lipid membrane scaffolds, the ERLINs may play a role in both morphogenesis of the ER and lipid droplet (LD) formation, two processes that have already been linked to HSP. In agreement with this hypothesis, we recently found that upon depletion of the ERLIN complexes in HeLa cells, the peripheral ER undergoes a remarkable structural rearrangement, characterized by a proliferation of flat sheet-like structures that substitute ER tubules. Furthermore, we established that both ERLIN1 and ERLIN2 interact with seipin, the protein product of the BSCL2 gene, and promote seipin stability in the ER. Seipin is involved in LD biogenesis and in maintaining the contacts between the ER and the LDs, and is itself mutated in some forms of HSP. Here, we aim to investigate the molecular mechanisms by which the ERLIN complexes regulate ER morphogenesis by using a combination of candidate molecule approaches and of unbiased proteomics and lipidomics strategies. We will define the protein and lipid scaffolding functions of ERLINs in the ER and how they affect stability in the ER membrane of specific proteins, such as seipin. Finally, to investigate the role of the ERLIN complexes in vivo in the nervous system and assess if altered pathways identified in vitro are relevant for the degeneration of long motor axons, we will develop and characterize Erlin1-deficient, Erlin2-deficient, and double Erlin1/2-deficient mice.

• DFG Programme: Research Grants