The Schmidt laboratory: Regulation of cellular lipid homeostasis

Sphingolipids are an essential class of lipids characterized by a unique sphingoid long chain base backbone linked to fatty acids by an amide linkage. Sphingolipids function as structural components of all cellular membranes, which are particularly indispensable for myelination in the nervous system, and they are also important signaling molecules. The biosynthesis of sphingolipids is initiated at the endoplasmic reticulum (ER) with the condensation of the amino acid L-serine and palmitic acid by the enzyme serine-palmitoyl-coenzym A transferase (SPT), which forms the first precursor of sphingoid long chain bases. This reaction is rate-limiting for sphingolipid synthesis and tightly regulated, because accumulation of sphingolipids or especially their synthesis intermediates is detrimental for cells, and associated with a number of diseases frequently including neurodegeneration (e.g. Gaucher and Fabri’s disease or hereditary sensory and autonomic neuropathy type 1 (HSAN1)).

SPT activity is regulated by the evolutionary conserved family of Orm1-like proteins, of which humans possess three paralogues (ORMDL1-3). They are membrane proteins of the ER, which associate with the transmembrane domain of SPT and thereby inhibit its catalytic activity. Why the genomes of most organisms encode more for than one ORMDL paralogue is not understood. Genetic mutations affecting the interaction of ORMDL family proteins with the SPT are of high pathological relevance. Loss of this regulatory module and hence uncontrolled synthesis of sphingolipid precursors is likely causative for a subtype of amyotrophic lateral sclerosis (ALS; Mohassel et al., 2021, Nature medicine), whereas increased expression of ORMDL3 is associated with several common inflammatory diseases, including childhood asthma (Moffatt et al., 2007, Nature) and IBD (MacGovern et al., 2010, Nature genetics).

The regulation of SPT by ORMDL proteins is best characterized in the budding yeast S. cerevisiae (See Fig. 6). Yeast has two ORMDL proteins, Orm1 and Orm2, which are under the control of plasma membrane stress signaling via the protein kinases TORC2 and Ypk1. Ypk1 phosphorylation causes dissociation of Orm1/2 and activates the SPT complex (Breslow et al., 2010, Nature), however, this phospho-regulation is only conserved in fungal species. Recently, we described an additional level of regulation of Orm proteins by translocation from the ER and degradation by the endosome and Golgi-associated degradation (EGAD; Schmidt et al., 2019, EMBO J.; Schmidt et al., 2020, JBC). This is the first reported example of a mode of regulation that is not shared by all ORMDL paralogs, because only Orm2 is exported and degraded, while Orm1 is stable. If human ORMDL proteins are also regulated by subcellular transport and proteolysis is currently unclear.

In my lab, we study the regulation of SPT by ORMDL-family proteins particularly in the light of differences between the paralogs, to understand why life typical relies on more than one ORMDL protein. We attempt to address fundamental research questions initially in budding yeast as an easily controllable model systems, and subsequently see if they are conserved in humans. Our goal is to discover how individual ORMDL paralogues may contribute to the homeostatic regulation of sphingolipid metabolism, and how their malfunction leads to human diseases.


Fig. 6: Regulation of serine palmitoyl-CoA transferase (SPT) activity by ORMDL family proteins in yeast cells (EGAD, endosome- and
Golgi-associated degradation; 3A, non-phosphorylatable Orm2 mutant; 3D, phospho-mimetic Orm2 mutant)

Publications

TOR complex 2 (TORC2) signaling and the ESCRT machinery cooperate in the protection of plasma membrane integrity in yeast. Schmidt O*, Weyer Y, Sprenger S, Widerin MA, Eising S, Baumann V, Angelova M, Loewith R, Stefan CJ, Hess MW, Fröhlich F, Teis D. J Biol Chem. 2020 Aug 21;295(34):12028-12044. doi: 10.1074/jbc.RA120.013222. Epub 2020 Jul 1. PMID: 32611771

Endosome and Golgi-associated degradation (EGAD) of membrane proteins regulates sphingolipid metabolism. Schmidt O, Weyer Y, Baumann V, Widerin MA, Eising S, Angelova M, Schleiffer A, Kremser L, Lindner H, Peter M, Fröhlich F, Teis D. EMBO J. 2019 Aug 1;38(15):e101433. doi: 10.15252/embj.2018101433. Epub 2019 May 27. PMID:31368600 

Complementary α-arrestin-ubiquitin ligase complexes control nutrient transporter endocytosis in response to amino acids. Ivashov V, Zimmer J, Schwabl S, Kahlhofer J, Weys S, Gstir R, Jakschitz T, Kremser L, Bonn GK, Lindner H, Huber LA, Leon S, Schmidt O*, Teis D. 2020 Aug 3;9:e58246. doi: 10.7554/eLife.58246.PMID: 32744498


Collaborations

Florian Fröhlich, Osnabrück University, DE
Maria Bohnert, Münster University, DE
Robbie Loewith, University of Geneva, CH
Matthias Peter, ETH Zurich, CH


Funding

Lipotype – Lipid excellence award 2019 (#2)

FWF P36187-B “individual functions of Orm/ORMDL family proteins in membrane homeostasis”

 

Team and contact

Assoc. Prof. Dr. Oliver Schmidt
Email: oliver.schmidt@i-med.ac.at       
Phone: +43 512 9003 70189
Google Scholar: https://scholar.google.com/citations?user=PHkoQ6cAAAAJ&hl=en
ORCID: https://orcid.org/0000-0002-7921-4663

NamePositionContact
Oliver Schmidtgroup leaderoliver.schmidt@i-med.ac.at     
Jana BleherMSc studentjana.bleher@student.uibk.ac.at