A critical role for the ER membrane complex (EMC) in lipid homeostasis
Abstract The ER membrane complex (EMC) facilitates insertion of integral membrane proteins into the endoplasmic reticulum (ER) lipid bilayer. Recent years have seen significant progress in understanding the structural aspects of EMC, but the identity of EMC-client proteins and EMC’s functional roles throughout evolution remain less well understood. Here we delete the essential EMC3 subunit in the liver and adipose tissues of mice and examine the impact of EMC loss-of-function in a range of metabolic and lipid homeostasis models. The absence of EMC3 in either the liver or adipose tissues results in defective storage of triglycerides and perturbations in lipid droplet (LD) homeostasis. EMC-deficient adipose tissues have reduced ability to mediate fat storage in mice on a high-fat diet and are unable to support non-shivering thermogenesis. Proteomic analyses of EMC3-deficient tissues show reduced levels of FITM2, a key regulator of LD biogenesis and ER homeostasis, identifying FITM2 as an EMC client. Deletion of EMC3 in the Drosophila fat body reveals similar defects in LD homeostasis, which can be rescued by a FITM2 mutant whose biogenesis was EMC-independent. Together, our results indicate that the EMC plays a key evolutionarily conserved role in the biogenesis of machinery maintaining triglyceride storage in metazoans.
Authors
- Kvido Střı́šovský (ORCID: https://orcid.org/0000-0003-3677-0907)
- Román Fischer (ORCID: https://orcid.org/0000-0002-9715-5951)
- Darragh Patrick O'Brien (ORCID: https://orcid.org/0000-0003-4924-7795)
- Catarina J Gaspar (ORCID: https://orcid.org/0000-0002-5295-6165)
- Pedro Manuel Dias Neto Domingos (ORCID: https://orcid.org/0000-0003-4523-5631)
- Abdulbasit Amin (ORCID: https://orcid.org/0000-0001-5460-9581)
- Pedro Faísca (ORCID: https://orcid.org/0000-0002-3922-3602)
- Iolanda Vendrell (ORCID: https://orcid.org/0000-0001-7187-4061)
- Karina Serafim da Silva (ORCID: https://orcid.org/0000-0003-4854-9302)
- Colin Adrain (ORCID: https://orcid.org/0000-0001-7597-4393)
- Emma Burbridge (ORCID: https://orcid.org/0000-0002-4243-7193)
- Tiago Paixão (ORCID: https://orcid.org/0000-0003-2361-3953)
- Érika de Carvalho (ORCID: https://orcid.org/0000-0001-7909-6970)
- Maria João Amorim (ORCID: https://orcid.org/0000-0002-4129-6659)
- Marina Badenes (ORCID: https://orcid.org/0000-0001-6872-891X)
- John C. Christianson (ORCID: https://orcid.org/0000-0002-0474-1207)
- Richard LiIttle
Institutions
- Queen's University Belfast (GB)
- Genentech (US)
- Czech Academy of Sciences (CZ)
- Universidade Católica Portuguesa (PT)
- University of Oxford (GB)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- Gulbenkian Institute for Molecular Medicine (PT)
- Instituto de Tecnologia Química e Biológica António Xavier (PT)
- Universidade Nova de Lisboa (PT)
- Universidade Lusófona (PT)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-11-03
- DOI
- https://doi.org/10.1038/s41467-026-78684-6
- Citations
- 1
- Primary Topic
- Lipid metabolism and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 1.97