Orm/ORMDL proteins: Gate guardians and master regulators

Davis, Deanna; Muthukumar, Kaliappan; Wattenberg, Binks W.

doi:10.1016/j.jbior.2018.08.002

Cited by 63 publications

(60 citation statements)

References 90 publications

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“…However, the mammalian ORMDLs, although otherwise homologous to the yeast proteins, lack the N-terminal peptide region that is phosphorylated in yeast (reviewed in Ref. 17). This suggests that the mammalian ORMDL-SPT complex utilizes a distinct mechanism to both sense cellular sphingolipid and to relay that information to the ORMDL-SPT system.…”

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confidence: 99%

The ORMDL/Orm–serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes

Davis

Gable

Suemitsu

et al. 2019

Journal of Biological Chemistry

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Edited by George M. CarmanSphingolipids compose a lipid family critical for membrane structure as well as intra-and intercellular signaling. De novo sphingolipid biosynthesis is initiated by the enzyme serine palmitoyltransferase (SPT), which resides in the endoplasmic reticulum (ER) membrane. In both yeast and mammalian species, SPT activity is homeostatically regulated through small ER membrane proteins, the Orms in yeast and the ORMDLs in mammalian cells. These proteins form stable complexes with SPT. In yeast, the homeostatic regulation of SPT relies, at least in part, on phosphorylation of the Orms. However, this does not appear to be the case for the mammalian ORMDLs. Here, we accomplished a cell-free reconstitution of the sphingolipid regulation of the ORMDL-SPT complex to probe the underlying regulatory mechanism. Sphingolipid and ORMDL-dependent regulation of SPT was demonstrated in isolated membranes, essentially free of cytosol. This suggests that this regulation does not require soluble cytosolic proteins or small molecules such as ATP. We found that this system is particularly responsive to the pro-apoptotic sphingolipid ceramide and that this response is strictly stereospecific, indicating that ceramide regulates the ORMDL-SPT complex via a specific binding interaction. Yeast membranes harboring the Orm-SPT system also directly responded to sphingolipid, suggesting that yeast cells have, in addition to Orm phosphorylation, an additional Orm-dependent SPT regulatory mechanism. Our results indicate that ORMDL/Orm-mediated regulation of SPT involves a direct interaction of sphingolipid with the membrane-bound components of the SPT-regulatory apparatus. . 2 The abbreviations used are: LCB, long chain bases; SPT, serine palmitoyltransferase; scSPT, single chain SPT construct (SPTLC2-ssSPTa-SPTLC1 as a fusion protein in a single polypeptide); C(X), (phyto)ceramide-ceramide or phytoceramide, where X ϭ acyl chain length; TBS, Tris-buffered saline; PVDF, polyvinylidene difluoride.

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confidence: 99%

The ORMDL/Orm–serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes

Davis

Gable

Suemitsu

et al. 2019

Journal of Biological Chemistry

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“…3 E). When myriocin was added to the culture to inhibit SPT activity (Sun et al, 2012;Gururaj et al, 2013), cells reduced nonphosphorylated Flag-Orm2, likely as a compensatory response to boost sphingolipid synthesis (Breslow et al, 2010;Davis et al, 2018). The effect was also observed in seipin mutants, and the 3xFlag-Orm2 phosphorylation levels were comparable between wild-type and seipin mutants ( Fig.…”

Section: Seipin Mediates Sphingolipid Production Independently Of Thementioning

confidence: 87%

Seipin negatively regulates sphingolipid production at the ER–LD contact site

Lin

Pagac

et al. 2019

Journal of Cell Biology

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Seipin is known for its critical role in controlling lipid droplet (LD) assembly at the LD-forming subdomain of the endoplasmic reticulum (ER). Here, we identified a new function of seipin as a negative regulator for sphingolipid production. We show that yeast cells lacking seipin displayed altered sensitivity to sphingolipid inhibitors, accumulated sphingoid precursors and intermediates, and increased serine palmitoyltransferase (SPT) and fatty acid (FA) elongase activities. Seipin associated with SPT and FA elongase, and the interaction was reduced by inhibitors for sphingolipid synthesis in a concentration-dependent manner. We further show that the interactions of seipin with SPT and FA elongase occurred at ER–LD contacts and were likely regulated differentially. Further evidence indicated that LD biogenesis was intact when SPT activity was blocked, whereas excess sphingoid intermediates may affect LD morphology. Expression of human seipin rescued the altered sphingolipids in yeast seipin mutants, suggesting that the negative regulation of sphingolipid synthesis by seipin is likely an evolutionarily conserved process.

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“…IKZF3 is a transcriptional repressor with a key role in B-cell activation and differentiation 20 and T cell differentiation 21 . ORMDL3 is a central regulator of sphingolipid biosynthesis 22 and has also been proposed to negatively regulate store-operated calcium, lymphocyte activation and cytokine production 18,23 , while GSDMB can act as a pyroptotic protein 24 . Therefore one or more of these genes may be causal for T1D risk.…”

Section: Discussionmentioning

confidence: 99%

Specific type 1 diabetes risk genes underpin age-at-diagnosis and indicate joint defects in immunity, beta-cell fragility and responses to viral infections in early-onset disease

Inshaw

Cutler

Crouch

et al. 2019

Preprint

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ObjectiveImmunohistological analyses of pancreata from patients with type 1 diabetes suggest a stratification of islet pathology of both B and T lymphocyte islet inflammation common in children diagnosed at <7 years (<7 group), whereas B cells are rare in those diagnosed age ≥13 (≥13 group). Based on these observations, we sought to identify differences in genetic susceptibility between these age-at-diagnosis groups, to inform on the aetiology of the most aggressive form of type 1 diabetes that initiates in the first years of life.Research Design and MethodsUsing multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA region and 55 non-HLA regions) had significantly stronger effect sizes in the <7 group compared to the ≥13 group, using genotype data from 27,075 individuals (18,488 controls, 3,109 cases diagnosed at <7, 3,754 at 7-13 and 1,724 at ≥13).ResultsSix HLA haplotypes/classical alleles and seven non-HLA regions, one of which functions specifically in beta cells (GLIS3), and the other six likely affecting key T cell (IL2RA, IL10, SIRPG, IKZF3, THEMIS), thymus (THEMIS) and B cell development/functions (IKZF3, IL10) or in both immune and beta cells (CTSH) had stronger effects in the <7 group.ConclusionsIn newborn children with the greatest load of certain risk alleles, dysregulated response of immune and beta cells to environmental stresses such as virus infection, combine to cause a rapid loss of insulin production, driving down the age of type 1 diabetes diagnosis.

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Orm/ORMDL proteins: Gate guardians and master regulators

Cited by 63 publications

References 90 publications

The ORMDL/Orm–serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes

The ORMDL/Orm–serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes

Seipin negatively regulates sphingolipid production at the ER–LD contact site

Specific type 1 diabetes risk genes underpin age-at-diagnosis and indicate joint defects in immunity, beta-cell fragility and responses to viral infections in early-onset disease

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